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1 Picornaviridae [Enteroviruses &
Rhinoviruses] & coronaviruses
2 Viral agents of diarrhea
3 Hepatitis viruses
4 Rabies virus
5 Arboviruses & Roboviruses
6 Retroviruses [HIV/AIDS]
7 Oncogenic viruses & agents of slow infection
 Classification
 The Picornaviridae family contains 12 genera:
- Enterovirus: enteroviruses and rhinoviruses[two major
groups of human pathogens],
- Hepatovirus (hepatitis A virus),
- Kobuvirus (Aichi virus)
• Parechovirus (parechoviruses),
• Aphthovirus (foot-and-mouth disease virus virus of cattle),
and
- Cardiovirus (cardioviruses): encephalomyocarditis virus of
rodents
- The first four groups contain important human pathogens.
 Enteroviruses are transient inhabitants of the human
alimentary tract and may be isolated from the throat or
lower intestine.
 Rhinoviruses are isolated chiefly from the nose and throat.
3
Structure and composition
 Enteroviruses and rhinoviruses consists
of a capsid shell made up of four proteins
(VP1-VP4) arranged with icosahedral
symmetry around a (+)ssRNA.
 Parechoviruses are similar except that
their capsids contain only three proteins
because VP0 does not get cleaved into
VP2 and VP4.
 There is a prominent cleft or canyon
around each pentameric vertex on the
surface of the virus particle.
 The receptor binding site used to attach
the virion to a host cell is thought to be
located near the floor of the canyon.
 This location would presumably protect
the crucial cell attachment site from
structural variation influenced by
antibody selection in hosts because the
canyon is too narrow to permit deep
penetration of antibody molecules
4
5
 Picornavirus replication
 Occurs in the cytoplasm of cells
 First, the virion attaches to a specific
receptor in the plasma membrane.
 The receptors for poliovirus and human
rhinovirus are members of the
immunoglobulin gene superfamily, which
includes antibodies and some cell surface
adhesion molecules.
 In contrast, echoviruses recognize a
member of the integrin adhesion
superfamily.
 The viruses that cause hand-foot-and-
mouth disease (enterovirus 71 and
coxsackievirus A16) can both use two
receptors, SCARB2 and PSGL1.
 Receptor binding triggers a conformational
change in the virion which results in
release of the viral RNA into the cell
cytosol.
 VPg is removed from the viral RNA as it
associates with ribosomes.
6
 Picornaviruses---
 Many picornaviruses cause diseases in humans ranging from
severe paralysis to aseptic meningitis, pleurodynia,
myocarditis, vesicular and exanthematous skin lesions,
mucocutaneous lesions, respiratory illnesses,
undifferentiated febrile illness, conjunctivitis, and severe
generalized disease of infants.
 However, subclinical infection is far more common than
clinically manifest disease.
 Etiology is difficult to establish because different viruses
may produce the same syndrome, the same picornavirus
may cause more than a single syndrome, and some clinical
symptoms cannot be distinguished from those caused by
other types of viruses.
 The most serious disease caused by any enterovirus is
poliomyelitis.
 A worldwide effort is making progress toward the goal of
total eradication of poliomyelitis.
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 Enteroviruses
 Poliovirus, the prototypical enterovirus, can
cause a subclinical or mild illness, aseptic
meningitis, or paralytic poliomyelitis.
 The nonpolio viruses (group A and B
coxsackieviruses, echoviruses, enteroviruses)
are responsible for a wide spectrum of diseases
in persons of all ages, although infection and
illness occur most commonly in infants.

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 General Properties
 Typical enteroviruses
 Inactivated when heated at 55°C for 30 minutes,
but Mg2+, 1 mol/L, prevents this inactivation.
 Whereas purified poliovirus is inactivated by a
chlorine concentration of 0.1 ppm, much higher
concentrations of chlorine are required to
disinfect sewage containing virus in fecal
suspensions and in the presence of other organic
matter.
 Polioviruses are not affected by ether or sodium
deoxycholate.
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 Dissemination pathway for PV in human

Oral ingested PV invades into blood through alimentary tract (A) followed by
viremia.
The virus in the blood permeates BBB into CNS (B).
PV also invades into CNS directly by neural pathway through MNs from skeletal
muscle to CNS (C). 14
15
 Clinical Findings
 When an individual susceptible to infection is
exposed to the virus, the response ranges from
inapparent infection without symptoms to a mild
febrile illness to severe and permanent paralysis.
 Most infections are subclinical; only about 1% of
infections result in clinical illness.
 The incubation period is usually 7-14 days, but it
may range from 3 to 35 days.
 Poliovirus syndromes can be abortive;
nonparalytic; or paralytic [including spinal polio,
bulbar polio, and polioencephalitis]
16
 Mild disease [Abortive polio ]
 This is the most common form of disease.
 The patient has only a minor illness,
characterized by fever, malaise, drowsiness,
headache, nausea, vomiting, constipation, and
sore throat in various combinations.
 Neurologic symptoms are typically not
reported
 Recovery occurs in a few days.

17
 Nonparalytic Poliomyelitis (Aseptic Meningitis)
 Symptoms are similar to
those of abortive polio but
more intense; also, patients
report stiffness of the
posterior muscles of the
neck, trunk, and limbs
 The disease lasts 2-10 days,
and recovery is rapid and
complete.
 Poliovirus is only one of
many viruses that produce
aseptic meningitis.
 In a small percentage of
cases, the disease advances
to paralysis.
18
 Paralytic Poliomyelitis [Spinal polio]
 The predominating complaint is flaccid
paralysis resulting from lower motor neuron
damage.
 However, incoordination secondary to brain
stem invasion and painful spasms of
nonparalyzed muscles may also occur.
 The amount of damage varies greatly.
 Maximal recovery usually occurs within 6
months, with residual paralysis lasting much
longer.

19
 Polio---
 Bulbar polio severe type of polio which involves
cranial nerves, most commonly IX, X, and XII;
patients accumulate pharyngeal secretions,
have a nasal twang to the voice, and develop
paralysis of vocal cords, causing hoarseness,
aphonia, and, eventually, asphyxia
 Polioencephalitis is principally reported in
children; unlike in other forms of polio, seizures
are common and paralysis may be spastic

20
 Progressive Postpoliomyelitis Muscle Atrophy
 A recrudescence of paralysis
and muscle wasting has been
observed in individuals
decades after their
experience with paralytic
poliomyelitis.
 Although progressive
postpoliomyelitis muscle
atrophy is rare, it is a specific
syndrome.
 It does not appear to be a
consequence of persistent
infection but rather a result of
physiologic and aging changes
in paralytic patients already
burdened by loss of
neuromuscular functions.
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5 5

26
Polio is disease due to wild-type poliovirus infection no longer occurs in the Western
Hemisphere, and WHO international eradication program is making significant progress in
the rest of the world. 27
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 Coxsackieviruses
 Large subgroup of the enteroviruses,
 Classified into HEV groups A, B, and C.
 Tend to be more pathogenic than the echoviruses
even though they exhibit similar properties
 Produce a variety of illnesses in humans,
including aseptic meningitis and respiratory and
undifferentiated febrile illnesses.
 IPD: 2 to 9 days
 Clinical manifestations: diverse [range from mild
febrile illness to CNS, skin, cardiac, and
respiratory diseases] 29
 Coxsackie A
 Herpangina (vesicular pharyngitis),
 Hand-foot-and-mouth disease [HFMD, A16]
 Acute hemorrhagic conjunctivitis
 Aseptic meningitis [many A, mostly A7 and A9].
 Meningoencephalitis and paralysis

30
 Coxsackie B
 Pleurodynia (epidemic myalgia),
 Most common cause of viral heart diseases
[Myocarditis, pericarditis],
 Severe generalized disease of infants
 Aseptic meningitis (all B)
 Devil’s grip [Bornholm disease]: Severe
intercostal pain and fever
 Meningoencephalitis and paralysis [incomplete
and reversible unlike polio]
 Two top diseases: Myocarditis & Devil’s grip
31
 Laboratory diagnosis
1. Recovery of Virus
- Throat washings [first few days], Stools [first
few weeks], Nasal secretions [A21], CSF (Aseptic
meningitis], conjunctival swabs [hemorrhagic
conjunctivitis], Throat swabs
- Tissue culture [CPE within 5-14 days]
- Suckling mice [rare]
2. Nucleic Acid Detection: Reverse transcription
PCR tests, Real-time PCR
3. Serology: difficult [IF]
32
 Rhinoviruses [HRV]
 Responsible for more than one-half of cold-like illnesses
and cost billions of dollars annually in medical visits and
missed days of work.
 Common cold viruses.
 Most commonly recovered agents from people with mild
upper respiratory illnesses.
 Usually isolated from nasal secretions
 Also responsible for about half of asthma exacerbations.
 >150 serotypes are known.
 Can be divided into major and minor receptor groups.
 Viruses of the major group use intercellular adhesion
molecule-1 (ICAM-1) as receptor, and those of the minor
group bind members of the low-density lipoprotein
receptor (LDLR) family.
33
HRV asthma exacerbations

BEC, bronchial endothelial cell; LRT, lower respiratory tract; URT, upper respiratory tract.34
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38
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40
Summary
Virus Transmission Pathogenesis Diseases Treatment/prev
polio Fecal-oral Virus targets anterior horn Asymptomatic to FUO, -No antiviral
motor neurons aseptic meningitis, treatment
paralytic polio (flaccid -Live vaccine
paralysis: no sensory (sabin)
loss) -Killed vaccine
(salk)
Coxsackie A Fecal-oral -Fecal-oral spread with -hand-foot and mouth - no specific
potential dissemination to disease (A16) treatment
other organs -Herpangina -No vaccine
-Often asymptomatic with -Aseptic meningitis -Hand washing
viral shedding -Acute lymphoglandular
pharyngitis
-Common cold
Coxsackie B Fecal-oral -As above - bornholm disease - no specific
(devils grip treatment
-Aseptic meningitis -No vaccine
-Severe systemic disease -Hand washing
of newborns
-Myocarditis
Echoviruses Fecal-oral -As above -Fever and rash of -no specific
unknown origin treatment
-No vaccine
-Hand washing
41
 Summary---
Virus Transmission Pathogenesis Diseases Treatment/prevention

Rhinoviruses Respiratory -Acid-labile, grows @33oc -common cold -no specific treatment
-Over 100 serotypes -No vaccine
-Hand washing

HAV Fecal-oral -Virus targets hepatocytes - Infectious - no specific treatment

-Liver function is impaired hepatitis - Killed vaccine and hyper
immune serum

42
 Viral agents of diarrhea---
 In developing countries, it is estimated to cause
as many as 1.5 million deaths of preschool
children annually, of which rotavirus is
responsible for about 600,000 deaths.
 Caliciviruses contains noroviruses, the major
cause of non-bacterial epidemic gastroenteritis
worldwide.
 Astroviruses also cause gastroenteritis.
Viral agents of diarrhea---

 Reoviridae [Rotavirus]
 Adenoviridae [Adenovirus]
 Caliciviridae [Calcivirus]
 Astroviridae [Astrovirus]
 Reoviridae
 Divided into 15 genera
 Four of the genera are able to infect humans and
animals: Orthoreovirus, Rotavirus, Coltivirus, and
Orbivirus.
 The genera are divided into two subfamilies:
- Spinareovirinae [Orthoreovirus]
o Contains viruses with large spikes at the 12
vertices on the particle,
- Sedoreovirinae [Rotavirus]
o Appear more smooth, lacking the large surface
projections
 Outstanding characteristics of Reoviruses
 Genetic reassortment occurs readily
 Rotaviruses are the major cause of infantile
diarrhea
 Reoviruses are good models for molecular
studies of viral pathogenesis
 Rotavirus
 First isolated in 1973 in Australia from children with diarrhea by
Ruth Bishop at the Royal Children's Hospital in Melbourne.
 Leading cause of severe gastroenteritis among children aged <5
years worldwide, accounting for approximately 5% of child
deaths annually

 A major cause of diarrhea-associated hospitalizations and

deaths

 Antibody is present in most by age 3years

 Infections in adult humans and animals are also common.
Rotavirus biology
 Belongs to the family
Reoviridae genus Rotavirus.
 60-80nm particle having a
double layered capsid
 Non-enveloped
 Wheel shaped with radiating
spokes
 Icosahedral symmetry
 Its genome consists of 11 ds-RNA
segments that generate six
structural proteins (VP1, VP2,
VP3, VP4, VP6 & VP7) and six
nonstructural proteins (NSP1-6).
 Rotavirus classification
 Seven different groups (A to G) based on antigenic epitopes on the
internal structural protein VP6, three of which (groups A, B, and C)
infect humans.
 Group A rotaviruses
- The most frequent human pathogens.
- Endemic worldwide (represents >95% of currently identified strains
in humans)
- The leading cause of severe diarrhea among infants and children
- Accounts for about half of the cases requiring hospitalization.
 Group B
- has been found to cause human disease in China where there may be
annual outbreaks of severe adult and infant diarrhea.
- More characteristically, cause diarrhea in pigs.
 Group C is found worldwide.
 Groups D, E and F have not been found in humans.
Rotavirus Serotypes
 There are at least 15 different serotypes of
rotaviruses.
 14 G serotypes are based on G protein (GP7)
differences.
- Five predominant strains in the United States (G1,
G2, G3, G4, G9) account for 90% of isolates and
strain G1 accounts for 73% of infections.
 There are 20 P serotypes based on the P protein
(VP4) with P4 and P8 predominating.
 Common P/G combinations are P8G1, P8G2, P4G2
and P8G4
 Properties of rotavirus
 Rotaviruses are stable in the environment for
many months and are relative resistant to hand
washing.
 They are susceptible to agents such as 95%
ethanol, formalin and "Lysol".
 They are also unstable to pH below 2.
 Pathogenesis

Infect cells in the villi of the small intestine (gastric and colonic mucosa are spared).
Multiply in the cytoplasm of enterocytes and damage their transport mechanisms.
NSP4, is a viral enterotoxin and induces secretion by triggering a signal transduction pathway.
Damaged cells may slough into the lumen of the intestine and release large quantities of virus, which
appear in the stool
Viral excretion usually lasts from 2 to 12 days in otherwise healthy patients but may be prolonged in
those with poor nutrition.
Diarrhea caused by rotaviruses may be due to impaired sodium and glucose absorption as damaged
cells on villi are replaced by non-absorbing immature crypt cells.
 Epidemiology
 Found worldwide, causing major diarrhea-associated
hospitalization and 600,000-850,000 deaths per year.
 Sero-prevalence studies show that antibody is present in
most infants by age 3 years.
 In the U.S., there are 20 - 40 deaths per year with 50-
70,000 hospitalizations and 500,000 physician visits per
year.
 Infections occur in the winter months (November
through May).
 The patient is contagious from before the onset of
diarrhea to a few days after the end of diarrhea.
 Epidemiology---
 Rotaviruses infect children at a young age.
 Older infants and young children (4 months - 2 years) tend to
be more symptomatic with diarrhea.
 Young infants may be protected due to trans-placental transfer
of antibody.
 Asymptomatic infections are common, especially in adults.
 Many cases and outbreaks are nosocomial
 Group A infections are most common.
 Group B has been associated with outbreaks in adults in China
 Group C is responsible for sporadic cases of diarrhea in infants
around the world.
 Spread is mainly person to person via fecal-oral route and
through fomites.
 Spread by food and water is also possible
 Clinical findings
 Rotaviruses cause the major portion of diarrheal illness in infants
and children worldwide but not in adults
 IPD: 1–4 days.
 Typical symptoms include:
- Fever can be high grade (>39°c in 30% of patients) and vomiting
and nausea precedes diarrhea.
- Non-bloody diarrhea lasting 3-9 days, but longer in
malnourished and immune deficient individuals.
- Necrotizing enterocolitis and hemorrhagic gastroenteritis is seen
in neonates.
- Abdominal pain, and
- Dehydration is the main contributor to mortality.
- Secondary mal-absorption of lactose and fat, and chronic
diarrhea are possible.
Clinical findings---
 Diagnosis
 Rapid diagnosis can be obtained by antigen
detection in stool using ELISA (which uses a
monoclonal antibody) and LA.
 Several kits are commercially available.
 These detect only Group A rotavirus.
 Electron microscopy also detects non-Group A
viruses.
 Group A rotaviruses can be cultured in monkey
kidney cells.
 Epidemiologic studies use patterns of viral RNA
migration by gel electrophoresis
(electropherotyping).
Treatment and prevention
 Treatment is just supportive care with
rehydration (oral/intravenous).
 Antiviral agents not known to be effective of
spread
 Good hand washing technique is important.
 In addition, surfaces, toilets and toys should
be disinfected.
 Adequate chlorination of water can prevent
spread in the community.
Immunity
 Antibodies against VP7 and VP4 are partially
protective but the initial infection does not
lead to permanent immunity and re-infection
can occur at any age.
 However, subsequent infections are usually
less severe than the primary infection.
 Vaccine
1. RotaTeq
 It contains five reassortants (WC3 bovine rotavirus strain with surface
proteins of the G1-4 and P1A human serotypes.
 It does not contain preservatives or thimerosal.
 Three doses are given at 2, 4 and 6 months of age with the minimum
age for the first dose of 6 weeks.
 The efficacy is high with 98% reduction in severe rotavirus
gastroenteritis within the first year of vaccination and a 96%
reduction in hospitalization rate.
 There is also a 74 and 71% reduction of rotavirus gastroenteritis
within the first and second years after vaccination.
2. Rotarix
 a live, attenuated, monovalent vaccine that contains the G1P[8]
human rotavirus strain.
 Hospitalizations are reduced by 96% and severe rotavirus
gastroenteritis by 90%.
 The vaccine is also effective against rotavirus gastroenteritis of any
severity (79%).
 Adenoviruses
 The name “adenovirus” reflects the recovery of
the initial isolate from explants of human
adenoids.
 Many infections are subclinical, and virus may
persist in the host for months.
 About one-third of the 51 known human
serotypes are responsible for most cases of
human adenovirus disease.
 Valuable systems for molecular and biochemical
studies of eukaryotic cell processes.
 Useful vectors for gene therapy approaches.
Structure
 70–90 nm in diameter and display
icosahedral symmetry, with capsids
composed of 252 capsomeres.
 Non-enveloped.
 Unique among icosahedral viruses
having fiber projecting from each
of the 12 vertices, or penton bases
 The rest of the capsid is composed
of 240 hexon capsomeres.
 The hexons, pentons, and fibers
constitute the major adenovirus
antigens important in viral
classification and disease diagnosis.
 The DNA genome is linear and
double stranded.
 Structure---
 The penton base carries a toxin-like activity that
causes rapid appearance of cytopathic effects and
detachment of cells from the surface on which they
are growing.
 The fibers contain type specific antigens that are
important in serotyping.
 Fibers are associated with hemagglutinating activity.
 Because the hemagglutinin is type specific,
hemagglutination-inhibition tests are commonly used
for typing isolates.
 It is possible, however, to recover isolates that are
recombinants and give discordant reactions in
neutralization and hemagglutination inhibition
assays.
 Pathogenesis
 Adenoviruses infect and replicate in epithelial cells
of the respiratory tract, eye, gastrointestinal tract,
and urinary tract.
 Usually do not spread beyond the regional lymph
nodes.
 Group C viruses persist as latent infections for years
in adenoids and tonsils and are shed in the feces for
many months after the initial infection.
 Most human adenoviruses replicate in intestinal
epithelium after ingestion but usually produce
subclinical infections rather than overt symptoms.
Pathogenesis---
 Clinical Findings
 About one-third of the known human serotypes are
commonly associated with human illness.
 A single serotype may cause different clinical diseases
and, conversely, that more than one type may cause the
same clinical illness.
 Adenoviruses 1–7 are the most common types
worldwide and account for most instances of adenovirus
associated illness.
 Adenoviruses are responsible for about 5% of acute
respiratory disease in young children, but they account
for much less in adults.
 Most infections are mild and self-limited.
 The viruses occasionally cause disease in other organs,
particularly the eye and the gastrointestinal tract.
Respiratory diseases
 Typical symptoms include cough, nasal congestion, fever, and
sore throat.
 Most commonly manifested in infants and children and
usually involves group C viruses, especially types 1, 2, and 5.
 Infections with types 3, 4, and 7 occur more often in
adolescents and adults.
 Adenoviruses particularly types 3, 7, and 21 are thought to
be responsible for about 10–20% of pneumonias in
childhood.
 A mortality rate up to 10% in the very young.
 Patients of all ages were affected, including healthy young
adults.
 Adenoviruses types 4 and 7 and occasionally by type 3 cause
of an acute respiratory disease syndrome among military
recruits and occurs in an epidemic form under conditions of
fatigue, stress, and crowding soon after induction.
 Eye infections
 Mild ocular involvement
 Pharyngo-conjunctival fever tends to occur in outbreaks,
such as at children’s summer camps (“swimming pool
conjunctivitis”), and is associated with types 3 and 7.
 The duration of conjunctivitis is 1–2 weeks, and
complete recovery with no lasting sequelae is the
common outcome.
 Epidemic keratoconjunctivitis [types 8, 19, and 37]-
mainly in adults and is highly contagious.
 Adenoviruses can remain viable for several weeks on
sinks and hand towels, and these may be sources of
transmission.
 Characterized by acute conjunctivitis followed by
keratitis that usually resolves in 2 weeks but may leave
sub-epithelial opacities in the cornea for up to 2 years.
 Gastrointestinal disease
 Types 40 and 41 have been etiologically
associated with infantile gastroenteritis and
may account for 5–15% of cases of viral
gastroenteritis in young children.
 Abundantly present in diarrheal stools.
 The enteric adenoviruses are very difficult to
cultivate.
 Other diseases
 Immuno-compromised patients may suffer from a variety of casual and
severe adenovirus infections.
 The most common problem caused by adenovirus infection in
transplant patients is respiratory disease that may progress to severe
pneumonia and may be fatal.
 Children receiving liver transplants may develop adenovirus hepatitis in
the allograft.
 In addition, children with heart transplants who develop myocardial
adenovirus infections are at increased risk of graft loss.
 Pediatric recipients of hematopoietic stem cell transplants may develop
infections with a wide variety of adenovirus types.
 Patients with AIDS may experience adenovirus infections, especially in
the gastrointestinal tract.
 Types 11 and 21 may cause acute hemorrhagic cystitis in children,
especially boys.
 Virus commonly occurs in the urine of such patients.
 Laboratory diagnosis
 Duration of adenovirus excretion varies among
different illnesses:
- 1–3 days, throat of adults with common cold;
- 3–5 days, throat, stool, and eye, for
pharyngoconjunctival fever;
- 2 weeks, eye, for keratoconjunctivitis;
- 3–6 weeks, throat and stool of children with
respiratory illnesses;
- 2–12 months, urine, throat, and stool of
immunocompromised patients.
 Laboratory diagnosis---
 Detection, isolation, and identification of virus
 Cell culture in human cells.
 Primary human embryonic kidney cells are most
susceptible but usually unavailable.
 Human epithelial cell lines, such as HEp-2, HeLa, and KB,
are sensitive but are difficult to maintain without
degeneration for the length of time (28 days) required to
detect some slow-growing natural isolates.
 Immunofluorescence tests using an antihexon antibody
on infected cells.
 Hemagglutination-inhibition and neutralization tests
 shell vial technique: infectious adenovirus detection
 nasal epithelial cells from a patient may be stained
directly to detect viral antigens.
 PCR assays
 Laboratory diagnosis---
 Serology
- The complement-fixation test
- Neutralization or hemagglutination-inhibition
- The neutralization test is the most sensitive.
 Epidemiology
 Adenoviruses exist in all parts of the world.
 They are present year round and usually do not cause community
outbreaks of disease.
 The most common serotypes in clinical samples are the low-numbered
respiratory types (1, 2, 3, 5, and 7) and the gastroenteritis types (40 and
41).
 Adenoviruses are spread by direct contact, by the fecal–oral route, by
respiratory droplets, or by contaminated fomites.
 Most adenovirus-related diseases are not clinically pathognomonic, and
many infections are subclinical.
 Infections with types 1, 2, 5, and 6 occur chiefly during the first years of
life; types 3 and 7 are contracted during school years; and other types
(such as 4, 8, and 19) are not encountered until adulthood.
 Although adenoviruses cause only 2–5% of all respiratory illness in the
general population, respiratory disease caused by types 3, 4, and 7 is
common among military recruits.
 Epidemiology---
 Eye infections can be transmitted in several ways, but
hand-to-eye transfer is particularly important.
 Outbreaks of swimming pool conjunctivitis are
presumably waterborne, usually occur in the summer, and
are commonly caused by types 3 and 7.
 Epidemic keratoconjunctivitis is a highly contagious and
serious disease.
 The disease, caused by type 8,
 More recently, adenovirus types 19 and 37 have caused
epidemics of typical epidemic keratoconjunctivitis.
 Outbreaks of conjunctivitis traced to ophthalmologists’
offices were presumably caused by contaminated
ophthalmic solutions or diagnostic equipment.
Epidemiology---
 The incidence of adenovirus infection in patients
undergoing bone marrow transplantation has
been estimated to be from about 5% to as high as
30%.
 The reported incidence is higher in pediatric
patients than in adults.
 Patients may develop fatal disseminated
infections.
 Types 34 and 35 are found most often in bone
marrow and renal transplant recipients.
 The most likely source of infection in transplant
patients is endogenous viral reactivation, although
primary infections may be a factor in the pediatric
population.
 Treatment and prevention
 No specific treatment for adenovirus infections.
 Careful hand washing is the easiest way to prevent infections.
 Environmental surfaces can be disinfected with sodium hypochlorite.
 In group settings, paper towels may be advisable because dirty towels
can be a source of infection in outbreaks.
 The risk of waterborne outbreaks of conjunctivitis can be minimized by
chlorination of swimming pools and waste water.
 Strict asepsis during eye examinations, coupled with adequate
sterilization of equipment, is essential for the control of epidemic
keratoconjunctivitis.
 Attempts to control adenovirus infections in the military have focused
on vaccines.
 Live adenovirus vaccine containing types 4 and 7, encased in gelatin-
coated capsules and given orally, was introduced in 1971.
 In this way virus bypasses the respiratory tract, where it could cause
disease, and is released in the intestine, where it replicates and induces
neutralizing antibody.
 It does not spread from a vaccinated person to contacts.
 Caliciviruses
 Caliciviridae are important agents of viral
gastroenteritis in humans.
 The most significant members are the
noroviruses, the prototype strain being Norwalk
virus.
 Classification
 The family Caliciviridae is divided into five genera:
1. Norovirus [Norwalk viruses]
2. Sapovirus [Sapporo-like viruses]
3. Nebovirus [bovine enteric viruses];
4. Lagovirus [rabbit hemorrhagic disease virus]
5. Vesivirus [vesicular exanthem virus of swine, feline
calicivirus, and marine viruses found in pinnipeds,
whales, and fish]
 The first two genera contain human viruses that cannot
be cultured; the latter two genera contain animal strains
that can be grown in vitro.
 Rabbit hemorrhagic disease virus was introduced in 1995
in Australia as a biologic control agent to reduce that
country’s population of wild rabbits.
 Calciviruses
 Human calicivirus serotypes are not defined.
 Multiple genotypes of noroviruses have been detected.
 Three geno-groups are associated with human
gastroenteritis, designated GI, GII, and GIV.
 Since 2001, genotype GII viruses have caused most viral
gastroenteritis outbreaks worldwide.
 Noroviruses appear to undergo antigenic drift over time,
probably in response to population immunity.
 Cellular receptors for noroviruses are histo-blood group
antigens that are expressed on the mucosal epithelia of
the digestive tract.
 A person’s secretor status is controlled by the
fucosyltransferase 2 gene; secretor-negative individuals
are resistant to infection with Norwalk virus.
 Clinical findings
 Noroviruses (Norwalk virus) are the most important cause of
epidemic viral gastroenteritis in adults.
 Epidemic non-bacterial gastroenteritis is characterized by (1)
absence of bacterial pathogens, (2) gastroenteritis with rapid
onset and recovery and relatively mild systemic signs, and (3)
an epidemiologic pattern of a highly communicable disease
that spreads rapidly with no particular predilection in terms of
age or geography.
 Various descriptive terms have been used in reports of
different outbreaks (eg, epidemic viral gastroenteritis, viral
diarrhea, winter vomiting disease) depending on the
predominant clinical feature.
 Norwalk viral gastroenteritis has an incubation period of 24–48
hours.
 The onset is rapid, and the clinical course is brief, lasting 12–60
hours; symptoms include diarrhea, nausea, vomiting, low-
grade fever, abdominal cramps, headache, and malaise.
 Clinical findings---
 The illness can be incapacitating during the
symptomatic phase, but hospitalization is rarely
required.
 Norovirus infections are more likely to induce
vomiting than those with Sapporo-like viruses.
 Dehydration is the most common complication in
young and elderly individuals.
 Viral shedding may persist for as long as 1 month.
 No sequelae have been reported.
 Laboratory diagnosis---
 RT-PCR is the most widely used technique for detection of human
caliciviruses in clinical specimens (feces, vomitus) and environmental
samples (contaminated food, water).
 Because of the genetic diversity among circulating strains, the choice
of PCR primer pairs is very important.
 Electron microscopy is frequently used to detect virus particles in
stool samples.
 However, norovirus particles are usually present in low
concentration (unless the sample was collected at peak viral
shedding) and are difficult to recognize; they should be identified by
IEM.
 ELISA immunoassays based on recombinant virus-like particles can
detect antibody responses, with a fourfold or greater rise in IgG
antibody titer in acute and convalescent-phase sera indicative of a
recent infection.
 Epidemiology---
 Human caliciviruses have worldwide distribution.
 Noroviruses are the most common cause of nonbacterial gastroenteritis in the
United States, causing an estimated 21 million cases annually.
 The viruses are most often associated with epidemic outbreaks of
waterborne, foodborne, and shellfish-associated gastroenteritis.
 All age groups can be affected.
 Outbreaks occur throughout the year, with a seasonal peak during cooler
months.
 Most outbreaks involve foodborne or person to person transmission via
fomites or aerosolization of contaminated body fluids (vomitus, fecal
material).
 Outbreaks in closed settings, such as cruise ships and nursing homes, are
typical.
 Characteristics of norovirus include a low infectious dose (as few as 10 virus
particles), relative stability in the environment, and multiple modes of
transmission.
 It survives 10 ppm chlorine and heating to 60°C; it can be maintained in
steamed oysters.
 Fecal–oral spread is probably the primary means of transmission of Norwalk
virus.
 Epidemiology---
 Among all foodborne disease outbreaks in the
United States (1998–2002), norovirus caused
30%.
 Ill food-service workers are often involved in
norovirus outbreaks.
 Viruses, predominantly norovirus, were involved
in 10% of waterborne disease outbreaks
associated with recreational water in the United
States (2003–2004).
 Epidemiology---
 Outbreaks of Norwalk gastroenteritis occur in
multiple settings.
 From 1996 to 2000, 39% occurred in
restaurants, 29% in nursing homes and
hospitals, 12% in schools and daycare centers,
10% in vacation settings, including cruise ships,
and 9% in other settings.
 In 2006, after Hurricane Katrina, a norovirus
outbreak occurred in a crowded evacuee
setting in Texas.
 Treatment and Control
 The low infectious dose permits efficient transmission of
the virus.
 Effective hand washing is probably the most important
method to prevent norovirus infection and transmission.
 Because of the infectious nature of the stools, care
should be taken in their disposal.
 Containment and disinfection of soiled areas and
bedding can help decrease viral spread.
 Careful processing of food and education of food
handlers are important because many foodborne
outbreaks occur.
 Purification of drinking water and swimming pool water
should decrease norovirus outbreaks.
 There is no vaccine.
 Astroviruses
 Derived from the Greek word
"astron" meaning star.
 Exhibit a star-like morphology with
five or six points in the EM
 Icosahedral, nonenveloped
 Contain +SS RNA, 6.4-7.4 kb in size.
 The family Astroviridae contains two
genera; all human viruses are
classified in the Mamastrovirus
genus.
 Astroviruses---
 At least eight serotypes of human viruses are
recognized by IEM and neutralization.
 Cause diarrheal illness and may be shed in
extraordinarily large quantities in feces.
 Transmitted by the fecal–oral route through
contaminated food or water, person-to-person
contact, or contaminated surfaces.
 Recognized as pathogens for infants and children,
elderly institutionalized patients, and
immunocompromised persons.
 May be shed for prolonged periods by
immunocompromised hosts.
 Astroviruses---
Sign and symptoms
 The main symptoms are diarrhoea, followed by
nausea, vomiting, fever, malaise and abdominal
pain.
 Some studies have shown that the duration of the
symptoms are approximately three to four days.
 Astrovirus infection is not usually a severe situation
and only in some rare cases leads to dehydration.
 Infected people do not need hospitalization because
symptoms reduce by themselves, after a short time.
 Astroviruses---
• Diagnosis
- EM, ELISA, IF, and PCR have all been used for
detecting virus particle, antigens or viral nucleic
acid in the stools of infected people.
- A method using real-time RT-PCR, which can
detect all human astrovirus genotypes, has been
reported
 Astroviruses---
Epidemiology
• Humans of all ages are susceptible to astrovirus infection, but
children, the elderly, and those that are immunocompromised are
most prone.
• The majority of children have acquired astrovirus antibodies by the
age of 5 and, looking at the pattern of disease, it suggests that
antibodies provide protection through adult life, until the antibody
titre begins to decline later in life.
• Astroviruses are associated with 5%-9% of cases of gastroenteritis in
young children.
• The occurrence of astrovirus infection varies depending on the
season.
- In temperate climates infection is highest during winter months in
contrast to tropical regions where prevalence is highest during the
rainy season.
• The main mode of astrovirus transmission is by contaminated food
and water.
• Young children in childcare backgrounds or adults in military barracks
are most likely to develop the disease.
Astroviruses---
• Prevention & treatment
- Inactivated vaccines are in use for certain
strains of Chicken Astrovirus (CastV).
- There are no anti-viral treatment against
infections but personal hygiene can reduce
the incidence of the illness.
 Hepatitis viruses
 Hepatitis can occur in the course of several
infections (CMV, yellow fever, EBV and rubella virus
infections)
 However, some viruses primarily infect the liver and
are called hepatitis viruses
 Include:
1. Hepatitis A virus (HAV)
2. Hepatitis B virus (HBV)
3. Hepatitis C virus (HCV)
4. Hepatitis D virus (HDV)
5. Hepatitis E virus (HEV)
2/3/2015 Tewelde Tesfaye
 Viral hepatitis---
 A systemic disease primarily involving the liver.
 Produce acute inflammation of the liver fever,
headache, anorexia, GI symptoms [nausea and
vomiting], dark urine and jaundice
 Regardless of the virus type, identical
histopathologic lesions are observed in the liver
during acute disease.
 In viral hepatitis, onset of jaundice is often
preceded by gastrointestinal symptoms such as
nausea, vomiting, anorexia, and mild fever.
 Jaundice may appear within a few days of the
prodromal period, but anicteric hepatitis is more
common.
97
98
S
P

C

99
HBV replication

100
 Classification of HBV
 The glycoproteins of HBs Ag contain:
 A group-specific antigen: “a”
 2 type-specific antigenic determinants: “d or y”
and “w or r”
 Based on this, the virus is divided into 4 major
serotypes:
 adw (Worldwide distribution)
 adr (Asia)
 ayw (Africa, India, Russia)
 ayr (Africa, India, Russia)

101
Traditionally HBV was classified into 4 subtypes or serotypes (adr, adw,
ayr, and ayw) based on antigenic determinants of HBsAg. 102
HBV immunology
HBV is not cytotoxic
In persons who fail to mount a
sufficiently vigorous immune
response to HBV during acute
infection, chronic infection
develops, and the persistent,
ineffective immune response
results in progressive liver
damage and fibrosis.

103
 HBV---
 HB is a global health problem:
 Infected two billion people (one-third of the global
population);
 Of these, >350 million suffer from chronic HBV
infection,
 Resulting in 1 million deaths each year, mainly from
cirrhosis or liver cancer.
 >10% of the global chronic HBV population resides
in India; infection may lead to liver damage that
results in acute or chronic hepatitis, liver cirrhosis,
and hepatocellular carcinoma (HCC) .

104
Pathogenesis of HBV
 HBV virion binds to a receptor at the surface of the
hepatocyte and enters the cell and begins to
replicate
 The copies of HBV genome integrate into the
hepatocyte chromosome and remain latent
 IPD: 40 -180 days, depending on the infectious
dose, the route of infection, and the person
 Cytopathic effect: The intracellular accumulation of
filamentous form of HBs Ag produces the ground-
glass appearance of affected heaptocyte.
 Single cells of liver parenchyma show ballooning
and form acidophilic (councilman) bodies as they
die.
105
Pathogenesis of HBV---
 Hypoimmune response:
 IFN↓, HLA-I↓ → CTL↓ (An insufficient T cell response)
→acute hepatitis/chronic hepatitis
 Immune complexes formed between HBs Ag and anti-
HBs (HBs Ab) contribute to the development of
hypersensitivity reactions, leading to problems such as
vasculitis, arthralgia, rash, and renal damage.
 Pathogenic damage caused by autoimmunity against
liver specific protein (LSP)
 Patients who have immunosuppressed states, such as
malnutrition, AIDS, and chronic illness, are more likely
to be asymptomatic carriers because their immune
system does not attack.
106
Pathogenesis of HBV---

107
HBV pathogenesis---

The seriousness of disease incidence is mainly related to various host

factors (age, gender, duration of infection, immune response) and viral
factors (viral load, genotype, quasispecies).

108
 Clinical syndromes
1. Acute infection
2. Chronic infection: Chronic persistent Hepatitis
B, Chronic active hepatitis
3. Co-infection or superinfection with hepatitis
delta virus (HDV)

109
Acute infection
 Subclinical infections: Fever, rash, arthritis
 Clinical infections: Malaise, anorexia, nausea
a) Anicteric infection: dark urine, elevated
transaminases
b) Icteric infection: jaundice, itching
 Fulminant hepatitis: Severe acute hepatitis with
rapid destruction of the liver
 Complications:
1. Serum sickness type syndrome
2. Polyarteritis nodosa
3. Membranous glomerulonephritis

110
 Chronic infection
1. Carriers: those persons in whom HBs Ag persists beyond 6 months
a) Simple carriers: HBe Ag absent but low titre of HBs Ag present in
blood
b) Super carriers: HBe Ag present in blood
2. Chronic persistent Hepatitis B
 Low grade “smoldering” hepatitis with slightly raised transaminases
 Can result in terminal hepatic failure
3. Chronic active hepatitis
Acute hepatitis state that continues without the normal recovery (lasts
longer than 6-12 months)
 Complications:
 Cirrhosis: permanent liver scarring and loss of hepatocytes
 Primary Hepatocellular Carcinoma (PHC): HBV may induce PHC by
promoting continued liver repair and cell growth in response to tissue
damage or by integrating into the host chromosome and stimulating
cell growth directly.

111
 Laboratory Diagnosis of HBV
 The initial diagnosis of hepatitis can be made on the basis
of the clinical symptoms and the presence of liver
enzymes in the blood.
 In viral hepatitis: ALT > AST
 In alcoholic hepatitis: AST > ALT
 The standard test of HBV is the detection of HBs Ag
 Direct Examination:
 Immunofluorescent staining:
- Infected heaptocyte shows HBV core protein in the nucleus
and infectious Dane particles in the cytoplasm
 Detection of viral DNA:
 DNA hybridisation
 PCR (Polymerase chain reaction)

112
Hepatitis B: Terminology and markers

113
HBs Ag [Australia antigen]
 Antigen found on surface of HBV
 May be spherical or filamentous
 Continued presence indicates carrier state
 HBs Ab (antigen to HBs Ag) provides immunity
to hepatitis B

114
 HBc Ag
 Antigen associated with core of HBV
 HBc Ab (antibody to HBc Ag) is positive during
window period
 IgM HBc Ab is an indicator of recent disease
 IgG HBc Ab signifies chronic disease

115
 HBe Ag
 Non-particulate form of HBc Ag
 Cleavage product of the viral core structural polypeptide
 Found dissolved in serum
 Important indicator of active viral replication and
therefore transmissibility
 High HBe Ag level indicates high infectivity
 HBe Ab (antibody to HBe Ag) indicates low transmissibility
 Pregnant mothers with HBeAg in their blood will almost
always transmit HBV to their offspring (90% transmission
rate), whereas mothers who have no HBeAg will rarely
infect the neonate (10% transmission rate

116
Hepatitis B serology [The HBV Panel]

117
HBV serology

118
HBV serology---
Tests Results Interpretation
HBsAg negative
Anti-HBc negative Susceptible
Anti-HBs negative

HBsAg negative
Anti-HBc positive Immune due to natural infection
Anti-HBs positive

HBsAg negative
Anti-HBc negative
Anti-HBs positive Immune due to hepatitis B vaccination**

119
 HBV serology---
HBsAg positive
Anti-HBc positive Acutely infected
IgM anti-HBc positive
Anti-HBs negative

HBsAg positive
Anti-HBc positive Chronically infected
IgM anti-HBc negative
Anti-HBs negative

Might be recovering from acute HBV infection / Might

be distantly immune and test not sensitive enough to
HBsAg negative detect very low serum anti-HBs / May be susceptible
Anti-HBc positive with a false positive anti-HBc / Might be undetectable
Anti-HBs negative level of HBs present in the serum and the person is
chronically infected
120
 Chronic hepatitis B
 A major global healthcare problem affecting 350 to
400 million people worldwide,
 Results in approximately one million deaths
annually, making it the world's tenth leading cause
of death.
 The progression of chronic hepatitis B is variable,
ranging from mild asymptomatic infection to severe
chronic liver disease.
 In about 15% to 25% of patients, ongoing viral
replication leads to serious complications including
hepatic decompensation, cirrhosis, and
hepatocellular carcinoma (HCC).
121
122
 Occult HBV infection [OBI]
 Those in which patients lack detectable HBsAg
but HBV DNA can be identified in liver or
serum samples.
 Occur frequently (~33%) in patients with
chronic HBV liver disease.
 Diagnosis of occult HBV infection requires
sensitive HBV-DNA PCR assay.

123
 Epidemiology of HBV
 The virus is extremely contagious
 Virus lives in all human body fluids (semen, urine,
saliva, tears, blood, breast milk, vaginal and
menstrual secretions, amniotic fluid, CSF, etc.)
 Blood and blood products constitute the most
important vehicle for parenteral transmission
 Saliva and semen are responsible for veneral
transmission
 Congenital or vertical transmission from carrier
mother is common

124
Epidemiology/HBV---
 Vulnerable group:
- Healthcare personnels,
- intravenous drug users,
- Hemophiliacs,
- Babies of mothers with chronic HBV,
- Renal dialysis patients,
- Individuals with multiple sex partners,
- Residents and staff members of institutions for the
mentally retarded
 High prevalence in developing countries
 Highest incidence in 15-19 years age
125
Transmission of HBV and spectrum of outcomes of
infection

126
HBV infection worldwide

Canada

India

Saudi Arabia
Africa

Brazil

127
 HB vaccination
1. Passive immunization: Hyperimmune HB
immunoglobulin (HBIG) prepared from donors with high
titres of anti-HBs Ag is indicated for:
- Non-immune individuals accidentally exposed to
potentially infectious material
- Individuals having an intimate personal contact with a
patient of carrier of HBV
- Neonates born to infectious mother
2. Active immunization: Subunit vaccines prepared by
cloning the surface antigen in yeast cells (Saccharomyces
cerevisiae) is indicated for infansts, children, especially
people in high risk groups (healthcare personnel), who are
HBs Ag negative, sexual partners of those known to be
infected with HBV, drug abusers, and patients requiring
frequent blood or blood product transfusion.
128
Treatment
α-IFN is used in the treatment of chronic
hepatitis B
Lamivudine and adefovir are nucleoside
analogues that inhibit viral DNA polymerase and
used for treatment

129
 Hepatitis type A
 Only one serotype is known.
 There is no antigenic cross-reactivity with HBV
or with the other hepatitis viruses.
 Various primate cell lines will support growth of
HAV, although fresh isolates of virus are difficult
to adapt and grow.
 No cytopathic effects are apparent.

130
Outcome of infection with hepatitis A virus

131
Hepatitis A
 Appears early in the disease and disappears
within 2 weeks after the onset of jaundice.
 Detected in the liver, stool, bile, and blood of
naturally infected humans and experimentally
infected nonhuman primates by immunoassays,
nucleic acid hybridization assays, or PCR.
 Detected in the stool from about 2 weeks before
the onset of jaundice up to 2 weeks after.

132
Clinical, virologic, and serologic events after
exposure to HAV

133
 Green land

India
Africa

Brazil

134
 Hepatitis type D (Delta Hepatitis)
 Classified in the Deltavirus genus, but not assigned to any virus
family.
 In blood, HDV (delta agent) contains delta-Ag (HDAg)
surrounded by an HBsAg envelope.
 (-)ssRNA, No homology exists with the HBV genome.
 HDAg is the only protein coded for by HDV RNA and is distinct
from the antigenic determinants of HBV.
 HDV is a defective virus that acquires an HBsAg coat for
transmission.
 It is often associated with the most severe forms of hepatitis in
HBsAg positive patients.

135
 Hepatitis D---
 Because HDV depends on a coexistent HBV infection,
acute type D infection occurs either as a simultaneous
infection (coinfection) with HBV or as a superinfection
of a person chronically infected with HBV.
 In the coinfection pattern, antibody to HDAg develops
late in the acute phase of infection and may be of low
titer.
 Assays for HDAg or HDV RNA in the serum or for IgM-
specific anti-HD are preferable.

136
 HD---
 All markers of HDV replication disappear during
convalescence; even the HDV antibodies may
disappear within months to years.
 However, superinfection by HDV usually results
in persistent HDV infection (more than 70% of
cases).
 High levels of both IgM and IgG anti-HD persist,
as do levels of HDV RNA and HDAg.
 HDV superinfections may be associated with
fulminant hepatitis.
137
CAR KENYA

138
 Hepatitis type C
 +SSRNA virus,
 Belongs to family Flaviviridae, genus Hepacivirus.
 Non-A, non-B (NANB) hepatitis agents, based on
serologic tests, were not related to HAV or HBV.
 Most cases of post-transfusion NANB hepatitis were
caused by HCV.

139
 HCV pathogenesis

-Hepatitis C virus (HCV) enters the liver through the hepatic artery and the portal vein, which
are the two blood vessels that transport blood into the liver.
-Acute HCV infection lasts from 0 to 24 weeks and often remains undetected
140
 Hepatitis C: Clinical feature
 The IPD is 2 weeks to 6 months.
 Most primary infections are asymptomatic[80%]
or clinically mild (20-30% have jaundice; 10-
20% have only nonspecific symptoms such as
anorexia, malaise, and abdominal pain).
 Those who are acutely symptomatic may exhibit
fever, fatigue, decreased appetite, nausea,
vomiting, abdominal pain, dark urine, grey-
coloured faeces, joint pain and jaundice
(yellowing of skin and the whites of the eyes).

141
 Hepatitis C---
 Most new infections are subclinical.
 Can be either “acute” or “chronic.”
o Acute Hepatitis C virus infection is a short-term illness
that occurs within the first 6 months after someone is
exposed to the Hepatitis C virus.
- Acute HCV infection is usually asymptomatic, and is only
very rarely associated with life-threatening disease.
- About 15-45% of infected persons spontaneously clear
the virus within 6 months of infection without any
treatment.
- For most people, acute infection leads to chronic
infection.
142
 Chronic Hepatitis C virus infection
 A long-term illness that occurs when the
Hepatitis C virus remains in a person’s body and
occurs in the majority (55-85%) of HCV
patients many are at risk of progressing to
chronic active hepatitis and
cirrhosis[scarring of the liver] (15-30%)
within 20 years.

143
 Hepatitis C---
 So, HCV infection can last a lifetime and lead to
serious liver problems, including cirrhosis or liver
cancer [HCC].
 About 25,000 individuals die annually of chronic
liver disease and cirrhosis in the United States;
HCV appears to be a major contributor to this
burden (~40%).
 Patients with chronic HCV are at increased risk
to develop acute liver failure if they develop
acute HAV infection.
 It is therefore recommended that all patients
with chronic HCV be vaccinated against HAV.
144
 Hepatitis type C---
 HCV displays genomic diversity, with different
genotypes (clades) predominating in different
parts of the world.
 The virus undergoes sequence variation during
chronic infections.
 This complex viral population in a host is referred
to as “quasi-species swarm.”
 This genetic diversity is not correlated with
differences in clinical disease, although
differences do exist in response to antiviral
therapy according to viral genotype.
145
 Geographical distribution
 Hepatitis C is found worldwide.
 The most affected regions are Central and East
Asia and North Africa.
 The hepatitis C epidemic can be concentrated in
certain high-risk populations (for example,
among people who inject drugs); and/or in
general populations.
 There are multiple strains (or genotypes) of the
HCV virus and their distribution varies by region.

146
 HCV genotypes

To date, more than 30 HCV genotypes have been identified

worldwide.
147
Transmission
 HCV is a bloodborne
 Most commonly transmitted through:
 Injecting drug use through sharing of injection
equipment;
 via the transfusion of unscreened blood and blood
products;
 sexually, and
 Passed from an infected mother to her baby [less
common].
 not spread through breast milk, food or water or by
casual contact such as hugging, kissing and sharing
food or drinks with an infected person.
148
Populations at increased risk of HCV infection:
1. People who inject drugs
2. Recipients of infected blood products or invasive
procedures in health-care facilities with
inadequate infection control practices
3. Children born to mothers infected with HCV
4. People with sexual partners who are HCV-
infected
5. People with HIV infection: Thus, co-infection with
HIV and HCV is common (50%-90%) among HIV-
infected injection drug users.
6. People who have used intranasal drugs
7. People who have had tattoos or piercings.

149
 Screening and diagnosis of HCV infection
 Due to the fact that acute HCV infection is
usually asymptomatic, early diagnosis of the
HCV infection is rare.
 In those people who go on to develop chronic
HCV infection, the infection may remain
undiagnosed, often until serious liver damage
has developed.
 WHO is launching new guidelines for the
screening, care and treatment of persons with
hepatitis C infection in April 2014.
150
Screening of HCV---
 HCV infection is diagnosed in 2 steps: Screening
for anti-HCV antibodies & NA test an
assessment of the degree of liver damage
 Screening for anti-HCV antibodies with a
serological test identifies people who have been
infected with the virus.
 If the test is positive for anti-HCV antibodies, a
nucleic acid test for HCV RNA is needed to confirm
chronic HCV infection because about 15-45% of
people infected with HCV spontaneously clear the
infection by a strong immune response without
the need for treatment.
 Although no longer infected, they will still test
positive for anti-HCV antibodies.
151
Screening of HCV---
 chronic hepatitis C infection(+)degree of liver
damage (fibrosis and cirrhosis)??
 Done by liver biopsy or through a variety of non-
invasive tests.
 In addition, identify the genotype
 6 genotypes of the HCV and respond differently to
treatment.
 Person can be infected with more than one
genotype.
 The degree of liver damage and virus genotype are
used to guide treatment decisions and management
of the disease.
152
 Lab diagnosis
 Serologic assays: ELISA
- Detect antibodies to HCV but do not distinguish among
acute, chronic,
- Anti-HCV antibodies can be detected in 50-70% of
patients at the onset of symptoms, but in others, antibody
appearance is delayed 3-6 weeks.
- Antibodies are directed against core, envelope, and NS3
and NS4 proteins and tend to be relatively low in titer.
 Nucleic acid-based assays (reverse transcription PCR)
- Detect the presence of circulating HCV RNA
- Useful for monitoring patients on antiviral therapy, and
- Used to genotype HCV isolates.

153
 Treatment
 Interferon + ribavirin
 Interferon is poorly tolerated in some patients.
 Despite these limitations, interferon and
ribavirin treatment can be life-saving.

154
 Prevention of HCV [WHO]
 There is no vaccine for hepatitis C
Primary prevention
hand hygiene: including surgical hand
preparation, hand washing and use of gloves;
safe handling and disposal of sharps and waste;
safe cleaning of equipment;
testing of donated blood;
improved access to safe blood;
training of health personnel.
155
 Prevention of HCV [WHO]---
Secondary and tertiary prevention: For people
infected with the hepatitis C virus
education and counselling on options for care
and treatment;
immunization with the hepatitis A and B
vaccines to prevent coinfection from these
hepatitis viruses to protect their liver;
early and appropriate medical management
including antiviral therapy if appropriate; and
regular monitoring for early diagnosis of chronic
liver disease.
156
 Hepatitis type E
 HEV, +SSRNA
 Belongs to family Hepeviridae, in the genus
Hepevirus.
 HEV is transmitted fecal-oral transmitted and
occurs in epidemic form in developing countries,
where water or food supplies are sometimes
fecally contaminated.
 Infection is typically self-limited

157
 Classification/HEV
 There is only one serotype of the virus and
 Classification is based on the nucleotide sequences
of the genome [G1-G4]
 Genotype 1: five subtypes,
 genotype 2: two
 genotypes 3: ten
 genotypes 4: seven
 For genotype 1, the age at which incidence peaks is
between 15 and 35 years and mortality is about 1%.
 Genotype 3 and 4: the most common in Japan; are
more common in people older than 60 years and
the mortality is between 5 and 10%.
158
 Distribution/HEV
 Genotype 1: tropical and several subtropical countries in
Asia and Africa.
 Genotype 2 : Mexico, Nigeria, and Chad.
 Genotype 3 : almost worldwide including Asia, Europe,
Oceania, North and South America.
 Genotype 4: limited exclusively to Asia.
 Genotypes 1 and 2 are restricted to humans and often
associated with large outbreaks and epidemics in
developing countries with poor sanitation conditions.
 Genotypes 3 and 4 infect humans, pigs and other animal
species and have been responsible for sporadic cases of
hepatitis E in both developing and industrialized
countries.
159
 HEV---
 Hepatitis E occasionally develops into an acute,
severe liver disease, and is fatal in about 2% of
all cases.
 Clinically, it is comparable to hepatitis A, but in
pregnant women the disease is more often
severe and is associated with a clinical syndrome
called fulminant hepatic failure.
 Pregnant women, especially those in the third
trimester, suffer an elevated mortality rate from
the disease of around 20%.

160
 Signs and symptoms
The IPD of hepatitis E varies from 3 to 8 weeks.
After a short prodromal phase symptoms lasting
from days to weeks follow.
They may include jaundice, fatigue and nausea.
The symptomatic phase coincides with elevated
hepatic aminotransferase levels.

161
HEV/Diagnosis
Viral RNA becomes detectable in stool and
blood serum during incubation period.
Serum IgM and IgG antibodies against HEV
appear just before onset of clinical symptoms.
Recovery leads to virus clearance from the
blood, while the virus may persist in stool for
much longer.
Recovery is also marked by disappearance of
IgM antibodies and increase of levels of IgG
antibodies.
162
 Epidemiology
 HEV causes around 20 million infections a year.
 These result in around three million acute
illnesses and as of 2010, 57,000 deaths annually.
 It is particularly dangerous for pregnant women,
who can develop an acute form of the disease
that is lethal in 20 % of cases.

163
 Animal reservoir
 Domestic animalsb[pigs] have been reported as
a reservoir for the HEV

164
Transmission/HEV
 Hepatitis E is prevalent in most developing countries,
and common in any country with a hot climate.
 Spread mainly by the fecal-oral route due to fecal
contamination of water supplies or food; person-to-
person transmission is uncommon.
 Outbreaks of epidemic hepatitis E most commonly occur
after heavy rainfalls and monsoons because of their
disruption of water supplies.

165
 Prevention & treatment
1. Sanitation
2. Vaccines
 A preventative vaccine (HEV 239) is approved
for use in China
3. Treatment
 Apart from supportive care, no specific
validated treatment

166
 Summary Viral hepatitis
Virus Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Common Infectious Serum Post - Delta Enteric
name transfusion/Non-
A Non-B
Family -Picornavirus -Hepadnavirus - Flavivirus -Unclassified -Calcivirus
features - ssRNA -ssDNA - ssRNA -Defective -ssRNA
- Naked -Enveloped - Enveloped - Circular -Naked
- ssRNA
- Enveloped
Transmission Fecal-oral Parentral, sexual Parentral, sexual Parentral, sexual Fecal-oral

Disease -Mild acute -Acute is -Acute usually -Co-infection -Normal

-No chronic occasionally subclinical with HBV patients are
severe -80% become -Often severe mild
-Chronic: 5-10% chronic -Cirrhosis - Pregnant
[adults], 90% -HCC -Fulminant patients
[infants] -Cirrhosis hepatitis severe
-HCC -No chronic
-Cirrhosis
167
 Summary ---
Virus Hepatitis Hepatitis B Hepatitis C Hepatitis D Hepatitis E
A
Mortality <5% 1-2% 0.5-1% High to very high -Normal patients: 1-
rate 2%
-pregnant: 20%
Diagnosis IgM to HBsAg, IgM to Ab to HCV, ELISA HDV Ab, HBsAg Ab to HEV, ELISA
HAV HBeAg

168
 Rhabidoviridae
 Family characteristics
- Very widely distributed in nature, infecting
vertebrates, invertebrates, and plants.
- Bullet shaped
- Enveloped, helical
 Viruses of medical importance
- Rabies virus [Genus Vesiculovirus]
- Vesicular stomatitis virus [Genus Lyssavirus]:
foot and mouth disease
 Rabies virus
 Infects all warm-blooded animals (dogs, cats, wolves,
foxes, cattle, skunks, raccoons; in all of which is fatal
 Worldwide, dogs are the primary reservoir [most
important source of infection]
 Rabies is an acute, fulminant, fatal encephalitis
- Primarily a disease of lower animals
- Present in the saliva and transmission is primarily
through animal bite
- In Ethiopia dogs are responsible for >98% of the cases &
Most of the people who die of rabies are under 40 years
of age, and among adults, the majority of these are
males, suggesting that the close contact the young men
have with dogs causes them to have a higher exposure
rate and more deaths from rabies.

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Structure of Rabies virus
Rhabidovirus, 75x180nm,
bullet shaped,
Enveloped, which is
covered with glycoprotein
spikes, which stimulate
neutralizing antibodies
(-)ssRNA,
 contain an RNA
polymerase

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 Rabies virus---
 Only one serotype; but with 2 biologic forms
1. Street virus
 Propagated in nature
 Infects by peripheral inoculation leading to encephalitis
 All lab animals are susceptible to IM or IC inoculation
 IPD 3-8 weeks
 Produces intacytoplasmic inclusion bodies (Negri bodies)
in the brain
2. Fixed virus: Results from repeated passage of the virus in
the brain of lab animals
 Attenuated and causes encephalitis only when inoculated
IC after a fixed IPD (4-6 days)
 No inclusion bodies

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 Reactions to physical and chemical agents
 Rabies virus
- Survives storage at 4°C for weeks and at 70°C for
years.
- Inactivated by CO2, so on dry ice it must be
stored in glass-sealed vials.
- Killed rapidly by exposure to ultraviolet radiation
or sunlight, by heat (1 hour at 50°C), by lipid
solvents (ether, 0.1% sodium deoxycholate), by
trypsin, by detergents, and by extremes of pH.
 Rabies Pathogenesis
The organ with the
highest titers of
virus is the
submaxillary
salivary gland.

- The closer you are bitten to the face or to the brain the more quickly you can develop
clinical rabies
- There is a higher attack rate and shorter IPD in persons bitten on the face or head; the
lowest mortality occurs in those bitten on the legs.
Rabies Pathogenesis---
 Rabies virus has not been isolated from the blood
of infected persons.
 Rabies virus produces a specific eosinophilic
cytoplasmic inclusion, the Negri body, in infected
nerve cells.
Negri bodies
- Filled with viral nucleocapsids.
- Pathognomonic of rabies but is not observed in at
least 20% of cases.
- The absence does not rule out rabies as a diagnosis.
- Their importance in rabies diagnosis has been
lessened by the development of the more sensitive
fluorescent antibody and RT-PCR diagnostic tests.
 Clinical findings
o IPD in humans is typically 1-3 months and usually shorter in children
than in adults.
o There are two general forms of clinical rabies: furious rabies (70%),
and paralytic rabies (30%).
o The clinical spectrum[furious rabies] can be divided into three
phases: - Lasting 2-10 days, may show nonspecific flu-
like illness: malaise, anorexia, headache,
Prodromal phase photophobia, nausea and vomiting, sore
[Furious throat, and fever.
Rabies]
- Lasts 2-7 days, patients show signs of nervous
70%
Neurologic phase system dysfunction such as nervousness,
apprehension, hallucinations, and bizarre
behavior.
- Followed by convulsive seizures or coma
Coma and death
 Clinical findings----
 With rare exception, rabies is always fatal when it
gets into the CNS (100%)
 Paralytic rabies occurs in about 30% of patients,
most frequently in those infected with bat rabies
virus.
 The disease course is slower, with some patients
surviving 30 days.
 Rabies should be considered in any case of
encephalitis or myelitis of unknown cause even in
the absence of an exposure history, and
particularly in a person who has lived or traveled
endemic areas.
Diagnosis [Rabies]
 Usually and unfortunately too late, postmortem
- Negri bodies in infected neurons [sites of viral
assembly], intracytoplasmic inclusion bodies
- Specimens include full thickness skin biopsy from
the nape of the neck including hair follicles,
corneal impression smears, saliva, CSF and serum
 Antigen detection by IF in skin biopsy and corneal
smears
 Virus isolation from saliva and CSF using
continuous cell culture or intracerebral
inoculation of mice
 RT-PCR
 ELISA
The highest case incidence occurs in Asia and Africa, where rabies potentially threatens
over 3 billion people.
- Rabies prevails to cause tens of thousands of deaths every year.
- The disease disproportionately affects poor, low-resource communities, particularly
children with 4 out of every 10 human deaths by rabies occurring in children younger than
15 years.
Treatment & prevention[Rabies]
- If signs are evident: None
- 100% vaccine-preventable disease
- If suspect:
o Wound cleaning with soap and water and irrigated by
virucidal agent (povidone iodine solution)
o Antibiotics and tetanus vaccine administration
o Post-exposure prophylaxis
 5 doses of rabies vaccine(human diplloid cell
vaccine[HDV], rabies vaccine adsorbed[RVA], purified
chick embryo cell vaccines [PCEC] (day of 3, 7, 14, 28))
 Passive Immunization with 1 dose of human rabies
immunoglobulin [HRIG], then
 Killed virus vaccine
 Control measures of rabies
 Pre-exposure vaccination is recommended for
persons at risk including veterinarians, animal
care personnel, and certain laboratory workers
 Destruction of stray dogs and quarantine of
imported dogs
 Vaccination of dogs, cats and other pets

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 Arbo & Roboviruses
 Have complex transmission cycles
 Have diverse physical and chemical properties
 Arthropod-borne viruses= arboviruses
- Transmission occurs by bloodsucking arthropods
 Rodent-borne viruses= roboviruses
- Rodent to rodent no arthropod
 Viral infection is usually persistent.
 Transmission occurs by contact with body fluids
or excretions.
184
Arboviruses & Roboviruses---
 All are RNA, enveloped viruses
 Classified in several virus families:
o Togaviridae
o Flaviviridae
o Bunyaviridae
o Reoviridae
o Arenaviridae
o Filoviridae

185
Arboviruses

186
 Arboviral diseases
• The major arbovirus diseases worldwide:
o Yellow fever,
o Dengue,
o B encephalitis,
o St. Louis encephalitis,
o Western equine encephalitis,
o Eastern equine encephalitis,
o Tick-borne encephalitis,
o West Nile fever, and
o Sand fl y fever

187
 Arboviral diseases---
 Arboviral diseases may be arbitrarily divided into three
clinical syndromes:
(1) Fevers of an undifferentiated type ± maculopapular rash
(2) Encephalitis high CFR
(3) Hemorrhagic fevers frequently severe & fatal
 Some arboviruses may be associated with more than one
syndrome (eg, dengue).
 The degree of viral multiplication and its predominant site
of localization in tissues determine the clinical syndrome.
 Thus, individual arboviruses can produce a minor febrile
illness in some patients and encephalitis or a hemorrhagic
diathesis in others.

188
 Arboviral diseases--- Dengue virus
Yellow fever virus
 Occur in distinct
geographic
distributions and
vector patterns. St. Louis encephalitis Japanese B encephalitis virus

 Each continent
tends to have its
own arbovirus
pattern, and Murray Valley encephalitis virus Tick-borne encephalitis virus

names are usually

suggestive,
including
Venezuelan West Nile virus
equine
encephalitis,
189
Arboviruses Infections with CNS involvement
• Four Arboviruses :
o St. Louis encephalitis virus (SLE)
o Eastern equine encephalitis (EEE)
o Western equine encephalitis (WEE)
o California Virus (CE) Lacrosse encephalitis

190
Transmission Cycles
 Man - arthropod -man
– e.g. dengue, urban yellow fever.
– Reservoir may be in either man or
arthropod vector.
– In the latter transovarial
transmission may take place.
 Animal - arthropod vector - man
– e.g. Japanese encephalitis, EEE,
WEE, jungle yellow fever.
– The reservoir is in an animal.
– The virus is maintained in nature
in a transmission cycle involving
the arthropod vector and animal.
– Man becomes infected incidentally.
 Both cycles may be seen with some
arboviruses such as yellow fever.

191
 Arthropod Vectors
Mosquitoes
oJapanese encephalitis, dengue, yellow fever, St. Louis encephalitis,
EEE, WEE, VEE
Ticks
oCrimean-Congo haemorrhagic fever, various tick-borne
encephalitis
 Sandflies
oSicilian sandfly fever, Rift valley fever.

192
Examples of Arthropod Vectors

Aedes Aegyti
Assorted Ticks

Culex Mosquito Phlebotmine Sandfly

193
 Animal Reservoirs
In many cases, the actual reservoir is not known.
The following animals are implicated as reservoirs:
oBirds Japanese encephalitis, St Louis encephalitis, EEE, WEE
oPigs Japanese encephalitis
oMonkeys Yellow Fever
oRodents VEE, Russian Spring-Summer encephalitis

194
 Roboviruses
 Major rodent-borne viral diseases include:
- Hantavirus infections,
- Lassa fever,
- South American hemorrhagic fevers
- Colorado tick fever
- African hemorrhagic fevers [Marburg and Ebola]
o Their reservoir hosts are unknown but are
suspected to be rodents or bats.

195
Flaviviridae
 Family characteristics
- Enveloped, icosahedral
- (+)ss RNA
- Replication cytoplasmic
- Arboviruses [mosquitoes]
 Viruses of medical importance
- St. Louis encephalitis virus [SLE]
- West Nile encephalitis virus [WNV]
- Dengue virus
- Yellow fever virus [YFV]
- Hepatitis C virus [HCV]
196
Transmission cycle of mosquito-borne flaviviruses
causing encephalitis
- Humans are dead-end
hosts and do not contribute
to perpetuation of virus
transmission.
- Wild birds are the most
common viremic hosts, but
pigs play an important role
in the case of Japanese
encephalitis virus.

197
Transmission cycle of tick-borne flaviviruses

- Virus is passed to succeeding tick

stages during molting (transstadial
transmission), as well as
transovarially to progeny of adult
ticks.
- Both male and female ticks are
involved in transmission.
- Tickborne encephalitis virus may
be transmitted to uninfected ticks
cofeeding on a vertebrate host
without the requirement for active
viremic infection of the host.

198
 Yellow fever virus (YFV)
 Belongs to Flaviviridae family
 Causes yellow fever [YF]
 There is a single serotype
 Multiply Animals & Mosquitoes and grows in
embryonated eggs, chick embryo cell cultures,
and cell lines [monkey, human, hamster, and
mosquito origin]

199
 Yellow fever [YF]
 Yellow jack or yellow plague
- An acute, febrile mosquito-borne illness that
occurs in tropics and subtropics of Africa and
South America
- Severe cases are characterized by liver and renal
dysfunction and hemorrhage, with a high
mortality rate.

200
YF
 Occurs in 2 major forms:
urban and jungle (sylvatic)
 Jungle YF
- Monkey-to-monkey by
arboreal mosquitoes (i.e,
Haemagogus, Aedes)
- Primarily a disease of
monkeys
- Man may become incidentally
infected on venturing into
jungle areas.
 Urban YF
- Involves person-to-person
transmission by domestic
Aedes mosquitoes (A. aegypti)
201
 YF
 Continues to infect and kill thousands of
persons worldwide because they have failed to
be immunized.
 Causes 200,000 infections & 30,000 deaths
every year, [~ 90% occur in Africa]
 All age groups are susceptible.

202
Common in tropical areas of South America and Africa, but not in Asia

203
 YF Pathogenesis
 Mosquito (♂) → Skin → local lymphnodes, liver,
spleen, kidney, bone marrow and Myocardium
[persists for days]
 Degenerative changes also occur in the spleen,
lymph nodes, and heart.
 Serious disease is characterized by hemorrhage
and circulatory collapse.
 Virus injury to the myocardium may contribute to
shock.

204
 Clinical Findings YF
 IPD is 3-6 days
 Classically patient with YF presents with fever, chills,
headache, dizziness, myalgia, and backache followed by
nausea, vomiting, and bradycardia.
 Most patients recover but in about 15% of cases, the
disease progresses to a more severe form, with fever,
jaundice, renal failure, and hemorrhagic manifestations.
 The vomitus may be black with altered blood.
 When the disease progresses to the severe stage (hepato-
renal failure), the mortality rate is high (20% or higher),
especially among young children and elderly adults.
 Death occurs on day 7-10 of illness.
 Regardless of severity, there are no sequelae; patients
either die or recover completely.
205
 YF Diagnosis
 Virus Isolation: From blood up to 5th day
→ Intracerebrally mouse →Recovery of virus
→NT
 Serology: HAI Titer rises rapidly
NT antibodies titer slow

206
 Prevention [YF]
• Vaccination
• Avoidance of mosquito bites in areas where
yellow fever is endemic.
• Institutional measures: vaccination
programmes and measures of controlling
mosquitoes.
• Programmes for distribution of mosquito nets
for use in homes are providing reductions in
cases of both malaria and yellow fever.

207
 YF Vaccine
 Live attenuated 17D viral strain vaccine
 Booster every 10 years
 Recommended for:– – travelers to regions in the
Yellow Fever endemic zone
 Required for: travelers to and from certain countries
 Vaccine may only be given at designated vaccination
center (must have a state stamp)

208
209
YF vaccine-adverse reactions
 25% mild adverse events
 Vaccine associated neurotropic disease
Contraindications
 Age < 9 months
 Immunocompromised
 Severe allergy to eggs
 Assess risk/benefits
 pregnancy, asymptomatic HIV w/ CD4 >200,
 age > 60 years

210
Dengue Fever (Break bone fever)
 Mosquito-borne [Aedes aegypti] tropical
disease caused by the dengue virus
 Flavivirus

Reside in water-filled containers

211
Distribution of Dengue

-Over 2 million cases per year.

-The number of cases of dengue fever has increased dramatically since the 1960s, with
between 50 and 528 million people infected yearly
-Become a global problem since the Second World War and is endemic in more than
110 countries
212
- SE Asia, Africa, Caribbean and S. America.
 Dengue---
 4 serotypes [1-4]
 Diseases begins 2-15 days after mosquito bite
 Classically, dengue presents with a high fever,
lymphadenopathy, myalgia, bone and joint pains, headache,
and a maculopapular rash.
 Severe cases may present with haemorrhagic fever and
shock with a mortality of 5-10%.
 Dengue haemorrhagic fever or Dengue shock syndrome
resulting in bleeding, low levels of where dangerously low BP occurs
blood platelets and blood plasma
leakage

213
Clinical course of dengue fever

214
215
Dengue shock syndrome

216
DHF - petechiae

217
 Dengue: Diagnosis
 Diagnosis is made by serology
- NT & HI antibodies within 7 days of fever
 Isolation of virus difficult
 PCR- rapid identification

218
 Treatment & Prevention
Treatment
 No specific antiviral therapy
 Supportive, using either oral or intravenous
rehydration for mild or moderate disease, and
intravenous fluids and blood transfusion for
more severe cases.
Prevention
 Vector control: depends on mosquito
eradication.
- Removal of all containers from their premises
which may serve as vessels for egg deposition.
 Repellents
 Clothing
 A live attenuated vaccine is being tried in
Thailand with encouraging results.

219
 St. Louis Encephalitis
 The most important cause of epidemic encephalitis
of humans in North America [caused about 10,000
cases and 1000 deaths since it was first recognized
in 1933]
 An average of 130 confirmed cases annually.
 Fewer than 1% of viral infections are clinically
apparent.
 The presence of infected mosquitoes is required
before human infections can occur, although
socioeconomic and cultural factors (air conditioning,
screens, mosquito control) affect the degree of
exposure of the population to these virus-carrying
vectors.
220
Flaviviridae---
Virus Vector Host (s) Disease Prevention
SLE Mosquito Birds Encephalitis Vector
control
WNE Mosquito Birds Encephalitis Vector
control

Dengue Mosquito Humans -Break bone fever: rash, muscle

[monkeys] and joint pain
- Dengue hemorrhagic
fever/shock: re-infection can
results in hemorrhage and shock,
particularly in children

YFV Mosquito Humans Yellow fever: liver, kidney, heart Vector

[monkeys] and GI (black vomit) damage control/live
attenuated
vaccine

221
 Togaviridae
 Family characterstics
- Enveloped, icosahedral
- Divided into two genera:
o Alphaviruses (arboviruses)
o Rubiviruses (rubella)
 Viruses of medical importance
- Alphaviruses: All are antigenically related [cross-reactions]
o Eastern Equine Encephalitis virus (EEE)
o Western Equine Encephalitis virus (WEE)
o Venezuelan Equine Encephalitis virus (VEE)
- Rubivirus
o Rubella

222
 Togaviridae---
Virus Vector Host Disease(s) Prevention
EEE, WEE, VEE Mosquito Birds, horses Viral encephalitis Killed vaccines
for EEE and WEE
Rubella None Humans -German measles Live, attenuated
-Congenital rubella vaccine
syndrome (CRS)

- CRS= Patent ductus arteriosus, pulmonary stenosis, cataracts, microcephaly,

deafness classical symptoms for CRS
-The effects are serious during the first 16 weeks of gestation.
-Rubella vs measles
• The rash for rubella which is basically a kind of macular rash starts on the
forehead and a kind of way working down
•For measles rash usually starts below the ears and behind the neck and works its
way down and eventually cover the face
•Much sicker with measles than with rubella [3 day measles, rubella measles or
the 7 day measles]

223
 Bunyaviridae
• Family characteristics
- Segmented, enveloped viruses
- Three segments, one ambisense
- Mostly arboviruses, except Hantavirus
• Viruses of medical importance
- California encephalitis
- La Crosse encephalitis
- Hantavirus (Sin Nombre)

224
Hantaviruses
 Enveloped ss RNA virus
 with a characteristic square grid-like structure
 Bunyaviridae
 Unlike other bunyaviridae, its transmission does not involve
an arthropod vector..
 Genome consists of three RNA segments: L, M, and S.

225
 History
 Haemorrhagic Fever with Renal Syndrome (HFRS: hantavirus disease)
first came to the attention of the West during the Korean war when
over 3000 UN troops were afflicted.
 Had been described by the Chinese 1000 years earlier.
 In 1974, the causative was isolated from the Korean Stripped field
mice and was called Hantaan virus.
 In 1995, a new disease entity called hantavirus pulmonary syndrome
was described in the “four corners” region of the U.S.

226
 Subtypes of hantaviruses associated with human disease
 Hantaan, Porrogia and related viruses
- This group is found in China, Eastern USSR, and some parts of S. Europe.
- Responsible for the severe classical type of hantavirus disease.
- Carried by stripped field mice. (Apodemus agrarius)
 Seoul type
- Associated with moderate hantavirus disease.
- Carried by rats and have a worldwide distribution.
- Has been identified in China, Japan, Western USSR, USA and S. America.
 Puumala type
- mainly found in Scandinavian countries, France, UK and the Western USSR. It is carried by
bank voles (Clethrionomys glareolus) and causes mild hantavirus disease (nephropathia
epidemica).
 Sin Nombre
- Found in many parts of the US, Canada and Mexico.
- Carried by the Deer Mouse (Peromyscus maniculatus) and causes hantavirus pulmonary
syndrome. 227
Rodent Carriers of Hantaviruses

Stripped field mouse (Apodemus agrarius)

Bank vole (Clethrionomys glareolus)

Deer Mouse (Peromyscus maniculatus) Rat (Rattus)

228
 Clinical Features of Hantavirus Disease
 The multisystem pathology of HVD is characterized by damage to capillaries
and small vessel walls, resulting in vasodilation and congestion with
hemorrhages.
 Classically, hantavirus disease consists of 5 distinct phases.
 Febrile phase - abrupt onset of a severe flu-like illness with a
erythematous rash after an incubation period of 2-3 days.
 Hypotensive phase - begins at day 5 of illness
 Oliguric phase: begins at day 9 of illness, the patient may develop acute
renal failure and shock, haemorrhages are usually confined to petechiae.
- The majority of deaths occur during the hypotensive and oliguric
phases
 Diuretic phase - this occurs between days 12-14 .
 Convalescent phase - this may require up to 4 months.

229
Hantavirus Pulmonary Syndrome (HPS)
 More than 250 cases of HPS have been reported throughout North
and South America with a mortality rate of 50%
 In common with classical HVD, HPS has a similar febrile phase.
 However, the damage to the capillaries occur predominantly in the
lungs rather than the kidney.
 Shock and cardiac complications may lead to death.
 The majority of HPS cases are caused by the Sin Nombre virus.
 The other cases are associated with a variety of other hantaviruses e.g.
New York and Black Creek Canal viruses.

230
 Diagnosis
 Serological diagnosis - a variety of tests including IF, HAI, SRH,
ELISA have been developed for the diagnosis of HVD and HPS.
 Direct detection of antigen - this appears to be more sensitive than
serology tests in the early diagnosis of the disease. The virus
antigen can be demonstrated in the blood or urine.
 RT-PCR- found to of great use in diagnosing hantavirus
pulmonary syndrome.
 Virus isolation - isolation of the virus from urine is successful
early in hantavirus disease. Isolation of the virus from the blood is
less consistent. Sin Nombre virus has never been isolated from
patients with HPS.
 Immunohistochemistry - useful in diagnosing HPS.

231
 Treatment and Prevention
• Treatment of HVD and HPS depends mainly on supportive measures.
 Ribavirin - reported to be useful if given early in the course of
hantavirus disease. Its efficacy is uncertain in hantavirus pulmonary
syndrome.
 Vaccination - an inactivated vaccine is being tried out in China. Other
candidate vaccines are being prepared.
 Rodent Control - control measures should be aimed at reducing contact
between humans and rodents.

232
 Bunyaviridae---
Virus Transmission Diseases
California and LaCrosse Mosquito Viral encephalitis
encephalitis
Hantavirus (Sin Nombrevirus Rodent excrement, Hantavirus pulmonary
without a name) four-corners region, syndrome: cough, myalgia
rainy season [leg, unique), dyspnea,
tachycardia, pulmonary
edema and effusion, and
hypotension (mortality
50%)

233
 Filoviridae
• Family characteristics
- enveloped, helical
- Filamentous
• Viruses of medical importance
African hemorrhagic fever
1. Ebola virus
2. Marburg virus

234
 Marburg virus
 Genetically unique zoonotic (or, animal-borne)
RNA virus of the filovirus family
 Marburg hemorrhagic fever (Marburg HF) is a
rare but severe hemorrhagic fever
- Affects both humans and non-human
primates.
- First recognized in 1967 in Marburg and
Frankfurt, Germany and Belgrade, Yugoslavia
(Serbia).
- Thirty-one people became ill, initially
laboratory workers followed by several medical
personnel and family members who had cared
for them and Seven deaths were reported.
235
Marburg virus---
• The reservoir host of Marburg virus is the
African fruit bat, Rousettus aegyptiacus
[widely distributed across Africa]
• Fruit bats infected with Marburg virus do not
to show obvious signs of illness.
• Primates (including humans) can become
infected with Marburg virus, and may develop
serious disease with high mortality.
• The virus is not known to be native to other
continents, such as North America.

236
 Marburg HF
 Typically appears in sporadic outbreaks throughout Africa;
laboratory confirmed cases have been reported in Uganda,
Zimbabwe, the Democratic Republic of the Congo, Kenya,
Angola, and South Africa.
 Many of the outbreaks started with male mine workers
working in bat-infested mines.
 The virus is then transmitted within their communities
through cultural practices, under-protected family care
settings, and under-protected health care staff.
 Cases of Marburg HF have occurred outside Africa, such as
during the 1967 outbreak, but are infrequent.
- In 2008, a Dutch tourist developed Marburg HF after returning
to the Netherlands from Uganda, and subsequently died.
- Also in 2008, an American traveler developed Marburg HF
after returning to the US from Uganda and recovered.

237
 Transmission/Marburg HF
 From its animal host to humans: Unknown
 However, unprotected contact with infected bat feces or
aerosols are the most likely routes of infection.
 After this initial crossover of virus from host animal to
humans, transmission occurs through person-to-person
contact.
- Direct contact to droplets of body fluids from infected
persons, or
- contact with equipment and other objects contaminated
with infectious blood or tissues.
 A common example is through caregivers in the home or
in a hospital (nosocomial transmission).

238
 Signs and Symptoms/Marburg HF
 After an incubation period of 5-10 days, symptom onset is
sudden and marked by fever, chills, headache, and myalgia.
 Around the fifth day after the onset of symptoms, a
maculopapular rash, most prominent on the trunk (chest,
back, stomach), may occur.
 Nausea, vomiting, chest pain, a sore throat, abdominal pain,
and diarrhea may then appear.
 Symptoms become increasingly severe and can include
jaundice, inflammation of the pancreas, severe weight loss,
delirium, shock, liver failure, massive hemorrhaging, and
multi-organ dysfunction.
 Because many of the signs and symptoms of Marburg
hemorrhagic fever are similar to those of other infectious
diseases such as malaria or typhoid fever, clinical diagnosis of
the disease can be difficult, especially if only a single case is
involved.
 The case-fatality rate is between 23-90%.
239
Risk of Exposure/Marburg
 Many bats hanging upside down ceiling of a
cavePeople who have close contact with African
fruit bats, humans patients, or non-human
primates infected with Marburg virus are at risk.
 Particular occupations, such as veterinarians and
laboratory or quarantine facility workers who
handle non-human primates from Africa, may also
be at increased risk of exposure to Marburg virus.
 Exposure risk can be higher for travelers visiting
endemic regions in Africa, including Uganda and
other parts of central Africa, and have contact
with fruit bats, or enter caves or mines inhabited
by fruit bats. 240
 Diagnosis/Marburg HF
 Signs and symptoms are similar to those of other more
frequent infectious diseases, such as malaria or typhoid fever,
making diagnosis of the disease difficult.
 This is especially true if only a single case is involved.
 However, if a person has the early symptoms of Marburg HF
and there is reason to believe that Marburg HF should be
considered, the patient should be isolated and public health
professionals notified.
 Samples from the patient can then be collected and tested to
confirm infection.
 ELISA,
 PCR; can be used to confirm a case of Marburg HF within a few
days of symptom onset.
 Virus isolation may also be performed but should only be done
in a high containment laboratory with good laboratory
practices.
241
 Treatment/Marburg HF
• No specific treatment
• Supportive hospital therapy should be utilized,
- balancing the patient's fluids and electrolytes,
- maintaining oxygen status and blood
pressure,
- replacing lost blood and clotting factors, and
- treatment for any complicating infections

242
Prevention/Marburg HF
 Not well defined, as transmission from wildlife to
humans remains an area of ongoing research.
 However, avoiding fruit bats, and sick non-human
primates in central Africa, is one way to protect
against infection.
 Barrier nursing techniques should be used to
prevent direct physical contact with the patient.
- wearing of protective gowns, gloves, and masks;
- placing the infected individual in strict isolation;
and sterilization or proper disposal of needles,
equipment, and patient excretions.
243
 Ebola Virus Disease

CDC Slides for U.S. Healthcare Workers*

January 16, 2015

Presentation is current through January 16, 2015 and will be updated every Friday by 5pm. For the most
up-to-date information, please visit www.cdc.gov/ebola.
*Presentation contains materials from CDC, MSF, and WHO
Centers for Disease Control and Prevention

Office of the Director

244
 Ebola Virus
 Prototype Viral Hemorrhagic Fever Pathogen
- Filovirus: enveloped, non-segmented, (-)ssRNA virus
- Affects human and non human primates
- Severe disease with high
case fatality
- MR can reach 90%
- Absence of specific treatment or vaccine???

245
 Ebola Virus classification---
Five known Ebola virus

 2014 West Africa Ebola outbreak caused by Zaire

ebolavirus species
 Ebola Virus
 Zoonotic virus – bats the most likely reservoir, although species
unknown
 Spillover event from infected wild animals (e.g., fruit bats,
monkey, duiker) to humans, followed by human-human
transmission

247
 Most affected regions by Ebola

Figure. Ebola virus disease (EVD)

cumulative incidence* — West Africa,
January 14, 2015

* Cumulative number of reported EVD cases to WHO

248
248
2014 Ebola Outbreak
Reported Cases in Guinea, Liberia, and Sierra Leone

This graph shows the cumulative reported cases in Guinea, Liberia, and Sierra Leone provided in WHO situation
reports beginning on March 25, 2014 through the most recent situation report on January 14, 2015.
249
249
EVD Cases and Deaths*
Reporting Date Total Cases Confirmed Cases Total Deaths

Guinea 13 Jan 15 2,825 2,525 1,829

Liberia 12 Jan 15 8,362 3,127 3,556

Sierra Leone 13 Jan 15 10,186 7,825 3,083

Mali 23 Nov 14 8 7 6

United Kingdom 29 Dec 14 1 1 0

Nigeria** 15 Oct 14 20 19 8

Spain** 27 Oct 14 1 1 0

Senegal** 15 Oct 14 1 1 0

United States** 24 Oct 14 4 4 1

TOTAL 21,408 13,510 8,483

Updated case counts available at http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html.

*Reported by WHO using data from Ministries of Health

**The outbreaks of EVD in Senegal, Nigeria, Spain, and the United States have ended.

250
250
 Ebola Virus Transmission
 Virus present in high quantity in blood, body fluids, and excreta
of symptomatic EVD-infected patients
 Opportunities for human-to-human transmission
 Direct contact (through broken skin or unprotected mucous
membranes) with an EVD-infected patient’s blood or body fluids
 Sharps injury (with EVD-contaminated needle or other sharp)
 Direct contact with the corpse of a person who died of EVD
 Indirect contact with an EVD-infected patient’s blood or body fluids via
a contaminated object (soiled linens or used utensils)
 Ebola can also be transmitted via contact with blood, fluids, or
meat of an infected animal
 Limited evidence that dogs become infected with Ebola virus
 No reports of dogs or cats becoming sick with or transmitting Ebola

251
Detection of Ebola Virus in Different
Human Body Fluids over Time

252
252
 Human-to-Human Transmission
 Infected persons are not contagious until onset of symptoms

 Infectiousness of body fluids (e.g., viral load) increases as patient

becomes more ill

 Remains from deceased infected persons are highly infectious

 Human-to-human transmission of Ebola virus via inhalation

(aerosols) has not been demonstrated

253
 Weaponization
 Ebolavirus is classified as a biosafety level 4 agent, as
well as a Category A bioterrorism agent by the CDC.
 It has the potential to be weaponized for use in
biological warfare, and was investigated by
Biopreparat for such use,
 But might be difficult to prepare as a weapon of mass
destruction because the virus becomes ineffective
quickly in open air.
Ebola Virus Pathogenesis
 Direct infection of tissues

 Immune dysregulation

 Hypovolemia and
vascular collapse

 Electrolyte abnormalities

 Multi-organ failure, septic

shock

 Disseminated
intravascular coagulation
(DIC) and coagulopathy
 Early Clinical Presentation
 Acute onset; typically 8–10 days after exposure
(range 2–21 days)
 Signs and symptoms
 Initial: Fever, chills, myalgias, malaise, anorexia
 After 5 days: GI symptoms, such as nausea, vomiting, watery diarrhea,
abdominal pain
 Other: Headache, conjunctivitis, hiccups, rash, chest pain, shortness of
breath, confusion, seizures
 Hemorrhagic symptoms in 18% of cases

 Other possible infectious causes of symptoms

 Malaria, typhoid fever, meningococcemia, Lassa fever and other
bacterial infections (e.g., pneumonia) – all very common in Africa

256
 Clinical Features
 Nonspecific early symptoms progress to:
 Hypovolemic shock and multi-organ failure
 Hemorrhagic disease
 Death

 Non-fatal cases typically improve 6–11 days after symptoms

onset

 Fatal disease associated with more severe early symptoms

 Fatality rates of 70% have been reported in rural Africa
 Intensive care, especially early intravenous and electrolyte
management, may increase the survival rate

257
Clinical Manifestations by Organ System
in West African Ebola Outbreak

Organ System Clinical Manifestation

General Fever (87%), fatigue (76%), arthralgia (39%), myalgia (39%)

Neurological Headache (53%), confusion (13%), eye pain (8%), coma (6%)

Cardiovascular Chest pain (37%),

Pulmonary Cough (30%), dyspnea (23%), sore throat (22%), hiccups (11%)

Gastrointestinal Vomiting (68%), diarrhea (66%), anorexia (65%), abdominal pain (44%),
dysphagia (33%), jaundice (10%)

Hematological Any unexplained bleeding (18%), melena/hematochezia (6%),

hematemesis (4%), vaginal bleeding (3%), gingival bleeding (2%),
hemoptysis (2%), epistaxis (2%), bleeding at injection site (2%),
hematuria (1%), petechiae/ecchymoses (1%)

Integumentary Conjunctivitis (21%), rash (6%)

WHO Ebola Response team. NEJM. 2014

258
258
Examples of Hemorrhagic Signs
Hematemesis

Gingival bleeding

Bleeding at IV Site

259
259
 Laboratory Findings

 Thrombocytopenia (50,000–100,000/mL range)

 Leukopenia followed by neutrophilia

 Transaminase elevation: elevation serum aspartate amino-

transferase (AST) > alanine transferase (ALT)

 Electrolyte abnormalities from fluid shifts

 Coagulation: PT and PTT prolonged

 Renal: proteinuria, increased creatinine

260
 EVD: Expected Diagnostic
Test Results Over Time
Critical information: Date of onset of fever/symptoms
IgM IgG
viremia

0 3 10 days post onset of symptoms

Fever

RT-PCR
ELISA IgM

ELISA IgG
IgM: up to 3 – 6 months IgG: 3 – 5 years or more (life-long persistance?)
261
 Ebola Virus Diagnosis
 Real Time PCR (RT-PCR)
 Used to diagnose acute infection
 More sensitive than antigen detection ELISA
 Identification of specific viral genetic fragments
 Performed in select CLIA-certified laboratories

 RT-PCR sample collection

 Volume: minimum volume of 4mL whole blood
 Plastic collection tubes (not glass or heparinized tubes)
 Whole blood preserved with EDTA is preferred
• Whole blood preserved with sodium polyanethol sulfonate (SPS), citrate,
or with clot activator is acceptable

262
 Other Ebola Virus Diagnostics
 Virus isolation
 Requires Biosafety Level 4 laboratory;
 Can take several days

 Immunohistochemical staining and histopathology

 On collected tissue or dead wild animals; localizes viral antigen

 Serologic testing for IgM and IgG antibodies (ELISA)

 Detection of viral antibodies in
specimens, such as blood, serum,
or tissue suspensions
 Monitor the immune response
in confirmed EVD patients

263
 Packaging & Shipping Clinical Specimens to CDC for Ebola Testing

http://www.cdc.gov/vhf/ebola/hcp/packaging-diagram.html
264
 Interpreting Negative Ebola RT-PCR Result
 If symptoms started ≥3 days before the negative result
 EVD is unlikely  consider other diagnoses
 Infection control precautions for EVD can be discontinued unless clinical
suspicion for EVD persists

 If symptoms started <3 days before the negative

RT-PCR result
 Interpret result with caution
 Repeat the test at ≥72 hours after onset of symptoms
 Keep in isolation as a suspected case until a repeat RT-PCR ≥72 hours after
onset of symptoms is negative

265
 Clinical Management of EVD:
Supportive, but Aggressive
 Hypovolemia and sepsis physiology
 Aggressive intravenous fluid resuscitation
 Hemodynamic support and critical care management if necessary
 Electrolyte and acid-base abnormalities
 Aggressive electrolyte repletion
 Correction of acid-base derangements
 Symptomatic management of fever and gastrointestinal
symptoms
 Avoid NSAIDS
 Multisystem organ failure can develop and may require
 Oxygenation and mechanical ventilation
 Correction of severe coagulopathy
 Renal replacement therapy

Reference: Fowler RA et al. Am J Respir Crit Care Med. 2014

266
 Investigational Therapies for EVD Patients
 No approved Ebola-specific prophylaxis or treatment
 Ribavirin has no in-vitro or in-vivo effect on Ebola virus
 Therapeutics in development with limited human clinical trial data
• Convalescent serum
• Therapeutic medications
o Zmapp – three chimeric human-mouse monoclonal antibodies
o Tekmira – lipid nanoparticle small interfering RNA
o Favipiravir – oral RNA-dependent RNA polymerase inhibitor

 Vaccines – in clinical trials

• Chimpanzee-derived adenovirus with an Ebola virus gene inserted
• Attenuated vesicular stomatitis virus with an Ebola virus gene inserted

References: 1Huggins, JW et al. Rev Infect Dis 1989; 2Jarhling, P et al. JID 2007; 3Mupapa, K et al. JID 1999 S18; 4Olinger, GG et al. PNAS 2012; 5Dye,
JM et al. PNAS 2012; 6Qiu, X et al. Sci Transl Med 2013; 7Qiu, X et al. Nature 2014; 8Geisbert, TW et al. JID 2007; 9Geisbert, TW et al. Lancet 2010;
10Kobinger, GP et al. Virology 2006; 11Wang, D et al. J Virol 2006; 12Geisbert, TW et al. JID 2011; 13Gunther et al. JID 2011; 14Oestereich, L et al.

Antiviral Res. 2014.

267
 Patient Recovery
 Case-fatality rate between 50-70% in the 2014 Ebola outbreak
 Case-fatality rate is likely much lower with access to intensive care
 Patients who survive often have signs of clinical improvement by
the second week of illness
 Associated with the development of virus-specific antibodies
 Antibody with neutralizing activity against Ebola persists greater than
12 years after infection

 Prolonged convalescence
 Includes arthralgia, myalgia, abdominal pain, extreme fatigue, and
anorexia; many symptoms resolve by 21 months
 Significant arthralgia and myalgia may persist for >21 months
 Skin sloughing and hair loss has also been reported

References: 1WHO Ebola Response Team. NEJM 2014; 2Feldman H & Geisbert TW. Lancet 2011; 3Ksiazek TG et al. JID 1999; 4Sanchez A
et al. J Virol 2004; 5Sobarzo A et al. NEJM 2013; and 6Rowe AK et al. JID 1999.

268
 EVD Algorithm for
Evaluation of the
Returned Traveler

**CDC Website to check current affected areas: www.cdc.gov/vhf/ebola

Algorithm available at http://www.cdc.gov/vhf/ebola/pdf/ebola-algorithm.pdf
Checklist available at http://www.cdc.gov/vhf/ebola/pdf/checklist-patients-evaluated-us-evd.pdf
269
 Interim Guidance for Monitoring and Movement
of Persons with EVD Exposure
 CDC has created guidance for monitoring people exposed
to Ebola virus but without symptoms
RISK LEVEL PUBLIC HEALTH ACTION
Monitoring Restricted Restricted
Public Activities Travel
HIGH risk Direct Active Monitoring Yes Yes
Case-by-case Case-by-case
SOME risk Direct Active Monitoring
assessment assessment
Active Monitoring
for some;
LOW risk No No
Direct Active Monitoring
for others
NO risk No No No
www.cdc.gov/vhf/ebola/hcp/monitoring-and-movement-of-persons-with-exposure.html
Leading vaccines
 Two leading vaccine candidates
1. Involves an adenovirus engineered to carry an Ebola
virus protein and is called ChAd3 [developed by the
US government in partnership with GSK]
2. Uses an Ebola virus protein spliced into a vesicular
stomatitis virus (VSV) and is called VSV-EBOV
[Canadian government]
 Prevention
 Avoid affected areas/people

 Hand washing

 Personal protective equipment (PPE)

272
Source:
http://www.cdc.gov/vhf/ebola/pdf/ppe-
poster.pdf Accessed Oct. 14, 2014

273
EVD Summary
 The 2014 Ebola outbreak in West Africa is the largest
in history and has affected multiple countries

 Human-to-human transmission by direct contact

 No human-to-human transmission via inhalation
(aerosols)
 No transmission before symptom onset
 Early case identification, isolation, treatment and
effective infection control are essential to prevent
Ebola transmission

274
EU research efforts at front line of fight against
Ebola
 Development of Ebola vaccines (3 projects)
 Scaling up vaccine manufacture (1 project)
 Compliance with vaccine regimens (1 project)
 Rapid diagnostic tests (3 projects)

Press release [Brussels, 16 January 2015]

 Filoviridae---
Virus Reservoir Transmission Disease Diagnosis Treatment/prevention

Ebola, Unknown Direct Fatal Level 4 Supportive/quarantine

marburg contact Hemorrhagic isolation,
(blood, fever ELISA,
secretions) PCR

277
Retroviruses
Name derived from an RNA dependent DNA Polymerase (Reverse
transcriptase): viral genome [RNA]DNA, which then integrates
into the host chromosomal DNA

Retro (Latin)=backwards

The reverse transcriptase is highly error prone and rapid genetic

variation is a feature of this group of viruses.

Enveloped, icosahedral capsid, diploid (+) ssRNA viruses

Associated with cancers, leukemias and the AIDS syndrome

2/3/2015 Tewelde Tesfaye 278

 Derivation of Names
 Retro (Latin)= backwards
 Onco (Greek, oncos)= tumor
 Spuma (Latin)= foam
 Lenti (Latin, lentus)= slow

2/3/2015 Tewelde Tesfaye 279

Classification [Retroviruses ]
Family: Retroviridae
Genus Features Examples
1. Alpharetrovirus Simple, Onco Avian leucosis virus, Rous sarcoma
virus [RSV]
2. Betaretrovirus Simple, Onco Mouse Mammary Tumor Virus

3. Gammaretrovirus Simple, Onco Mammalian leukemia, sarcoma viruses

4. Deltaretrovirus Complex, Onco Bovine Leukemia, Human T Cell
Leukemia (HTLV)
5. Epsilonretrovirus Complex, Onco fish viruses

6. Lentivirus Complex HIV, Visna, EIAV

7. Spumavirus Complex Simian Foamy Virus [foamy
degeneration of inoculated cells]
2/3/2015 Tewelde Tesfaye 280
 Classification---
 Viruses of medical importance
- Oncovirus group
 Human T-cell leukemia/lymphotropic [HTLV];
 Adult T-cell leukemia [High incidence in Japan,
Caribbean, Southern U.S]

- Lentivirus group
 Human immunodeficiency virus [HIV] Acquired
immunodeficiency syndrome [AIDS]

 Retroviruses may be grouped morphologically (types A,

B, C, and D); the vast majority of isolates display type C
characteristics.

2/3/2015 Tewelde Tesfaye 281

 Classification---
Exogenous Endogenous
Spread horizontally and behave as typical Transmitted vertically through the germ line
infectious agents. [from parent to offspring]

-Initiate infection and transformation only Not beneficial not pathogenic

after contact - Do not produce any disease and cannot
-The pathogenic retroviruses all appear to be transform cells in culture
exogenous viruses.

Gene sequences of exogenous viruses are
found only in infected cells.
Lentiviruses [HIV], Deltaretroviruses [HTLV]
Found in all cells of all individuals of a given
species
Betaretroviruses [human endogenous
retrovirus, HERV-K], Spumaviruses [simian
foamy virus, SFV], Gammaretroviruses
[HERV-F, H, I, E, R, W]

2/3/2015 Tewelde Tesfaye 282

HERV = human endogenous retrovirus

SFV = simian foamy virus

2/3/2015 Tewelde Tesfaye 283

 Host range
 The presence or absence of an appropriate cell surface
receptor is a major determinant of the host range of a
retrovirus.
 Infection is initiated by an interaction between the viral
envelope glycoprotein and a cell surface receptor.
 Ecotropic viruses infect and replicate only in cells from
animals of the original host species.
 Amphotropic viruses exhibit a broad host range (able to
infect cells natural host & heterologous species) because
they recognize a receptor that is widely distributed.
 Xenotropic viruses can replicate in some heterologous
(foreign) cells but not in cells of the natural host.
- Many endogenous viruses have xenotropic host ranges.
2/3/2015 Tewelde Tesfaye 284
 Oncogenic Potential
 Retroviruses that contain oncogenes are highly
oncogenic.
 Sometimes referred to as “acute transforming”
agents
 The viruses that do not carry an oncogene have a
much lower oncogenic potential.
 In the case of the acute transforming viruses, a
cellular gene has been inserted by recombination
into the viral genome and is expressed as a viral
gene under the control of the viral promoter.
 In the case of the slow transforming leukemia
viruses, the viral promoter or enhancer element is
inserted adjacent to or near the cellular gene in the
cellular chromosome.
2/3/2015 Tewelde Tesfaye 285
 Genetic content
Nondefective, replication-competent viruses Viruses carrying oncogenes

The oncogene
shaded: src, myc,
ras, mos, abl
oncogene

Moloney murine sarcoma

Abelson murine leukemia virus

2/3/2015 Tewelde Tesfaye 286

Human T-Lymphotropic Viruses [HTLVs]
 Four types of HTLVs: HTLV-1, HTLV-2, HTLV-3, and
HTLV-4
 HTLV-1Adult T-cell leukemia-lymphomas (ATL) &
nervous system degenerative disorder[tropical
spastic paraparesis]
 It does not carry an oncogene [Transactivating
regulatory genes may contribute to oncogenesis by
modulating cellular genes that regulate cell growth]
 HTLV-2, HTLV-3, and HTLV-4have not been
conclusively associated with a specific disease
 HTLV-1 and HTLV-2 share about 65% sequence
homology and display significant serologic cross-
reactivity.
2/3/2015 Tewelde Tesfaye 287
 HTLV---
 There are several genetic subtypes of HTLV-1, with
the major ones being subtypes A, B, and C
 The virus is distributed worldwide, with an
estimated 20 million infected individuals.
 Clusters of HTLV-associated disease are found in
certain geographic areas (southern Japan, Melanesia,
the Caribbean, Central and South America, and parts
of Africa).
 Although fewer than 1% of people worldwide have
HTLV-1 antibody, up to 5% of the population in
endemic areas may be sero-positive.
 ATL is poorly responsive to therapy.
 The 5-year survival rate for patients with this cancer
is <5%.
2/3/2015 Tewelde Tesfaye 288
 Clinical picture/HTLV
 The primary clinical feature is development of
progressive weakness of the legs and lower
body.
 The patient’s mental faculties remain intact.
Diseases
 HTLV-1-associated myelopathy/tropical spastic
paraparesis (HAM/TSP).
 Uveitis
 Infective dermatitis.

2/3/2015 Tewelde Tesfaye 289

 Transmission/HTLV
 Mother-to-child transmission via breast feeding
is an important mode [15–25%]
- Such early-life infections are associated with the
greatest risk of ATL.
 Blood transfusion is an effective means of
transmission, as are sharing blood contaminated
needles (drug abusers) and sexual intercourse.

2/3/2015 Tewelde Tesfaye 290

 Human immunodeficiency virus (HIV)
 Non-oncogenic cytolytic slow retroviruses that
cause acquired immunodeficiency syndrome
(AIDS)
 Millions are now infected worldwide; once
infected, individuals remain infected for life.
 Within a decade, if left untreated, develop fatal
opportunistic infections as a result of HIV
induced deficiencies in the immune system.
 The development of highly active antiretroviral
therapy (HAART) for chronic suppression of HIV
replication and prevention of AIDS has been a
major achievement in HIV medicine.
2/3/2015 Tewelde Tesfaye 291
 HIV Structure
surface
transmembrane

matrix protein
Capsid protein
nucleocapsid
protein

RT
Integrase
protease

2/3/2015 Tewelde Tesfaye 292

Products of HIV gene

2/3/2015 Tewelde Tesfaye 293

 HIV gene---
 Nef= negative factor
- Responsible for the virulence of the virus,
- Decreases CD4 & MHC I expression on host
cells,
- Manipulates T-cell activation pathways,
- Required for progression to full-blown AIDS.
 Long HIV infection if Nef gene is deleted

2/3/2015 Tewelde Tesfaye 294

 Classification
 HIV belongs to genus Lentivirus, family
Retroviridae
 There are two distinct types: HIV-1 and HIV-2.
 HIV-1 was isolated in 1983 and HIV-2 in 1986
 The two types are distinguished on the basis of
genome organization and phylogenetic
(evolutionary) relationships with other primate
lentiviruses.
 Sequence divergence between HIV-1 and HIV-2
exceeds 50%
2/3/2015 Tewelde Tesfaye 295
Comparison of HIV species
Species Virulence Infectivity Prevalence Inferred origin

HIV-1 High High Global

Common Chimpanzee

HIV-2 Lower Low West Africa

Sooty Mangabey

2/3/2015 Tewelde Tesfaye 296

 HIV-1 & HIV-2
 Based on env gene sequences, the
strains of HIV-1 can be classified into
four groups: the "major" group M, the
"outlier" group O and two new groups,
N and P
 M group is the most common type of
HIV, with more than 90% of HIV/AIDS
cases
 The predominant contains at least 10
subtypes or “clades” (A-J).
 Similarly, five subtypes of HIV-2 (A-E)
have been identified.
 Within each subtype there is extensive
variability.
 The genetic clades do not differ in
biology or pathogenesis.
2/3/2015 Tewelde Tesfaye 297
Distribution of HIV-1 subtypes
A : West Africa
B : Europe, the Americas, Japan, Thailand, and
Australia.
C : Southern Africa, Eastern Africa, India,
Nepal, and parts of China.
D : Eastern and central Africa.
E: has never been identified as a non-
recombinant, only recombined with subtype
A as CRF01_AE.
F: central Africa, South America and Eastern
Europe.
G (and CRF02_AG): Africa and central Europe.
H: limited to central Africa.
I: CRF04_cpx, with the cpx for a "complex"
recombination of several subtypes.
J: North, Central and West Africa, and the
Caribbean
K: limited to the Democratic Republic of
Congo and Cameroon.
2/3/2015 Tewelde Tesfaye 298
 HIV-1 & HIV-2---
 The organization of the genomes of primate
lentiviruses (human and simian) is very similar.
 One difference is that HIV-1 and the chimpanzee
virus carry a vpu gene, whereas HIV-2 and the
SIVsm[mucosal simian immunodeficiency virus]
group have a vpx gene.
 The sequences of the gag and pol genes are highly
conserved.
 There is significant divergence among the envelope
glycoprotein genes; the sequences of the
transmembrane protein portion are more conserved
than the external glycoprotein sequences (the
protein component exposed on the exterior of the
virus particle).
2/3/2015 Tewelde Tesfaye 299
 Disinfection and Inactivation
 HIV is inactivated by:
- Treatment for 10 minutes at room temperature with
10% household bleach, 50% ethanol, 35%
isopropanol, 1% Nonidet P40, 0.5% Lysol, 0.5%
paraformaldehyde, or 0.3% hydrogen peroxide.
- Exposure to undiluted bleach for at least 30 seconds
- Extremes of pH (pH 1.0, pH 13.0).
 Liquids or 10% serum by heating at 56°C for 10
minutes
- Lyophilized blood products would need to be heated
at 68°C for 72 hours
 The virus is not inactivated by 2.5% Tween 20.
2/3/2015 Tewelde Tesfaye 300
 HIV tropism
 Viral tropism refers to the cell types a virus infects.
 HIV can infect a variety of immune cells such as CD4+ T
cells, macrophages, and microglial cells.
 HIV-1 can be M-tropic [R5 viruses], T-tropic [X4 viruses],
or Dual-tropic [X4R5 viruses]
- Macrophage (M-tropic) strains or non-syncytia-inducing
strains (NSI) or R5 viruses use the β-chemokine receptor
CCR5 for entry and are, thus, able to replicate in
macrophages and CD4+ T cells.
- T-tropic isolates or syncytia-inducing (SI) or X4 viruses
strains replicate in primary CD4+ T cells as well as in
macrophages and use the α-chemokine receptor, CXCR4,
for entry.
- Dual-tropic are thought to be transitional strains of HIV-1
and thus are able to use both CCR5 and CXCR4 as co-
receptors for viral entry.
2/3/2015 Tewelde Tesfaye 301
 HIV tropism---
 Macrophages play a critical role in HIV infection
Appear to be the first cells infected by HIV and
perhaps the source of HIV production when
CD4+ cells become depleted in the patient.
With microglial cells are the cells infected by HIV
in the CNS.
Fuse into multinucleated giant cells that produce
huge amounts of virus in tonsils and adenoids of
HIV-infected patients,

2/3/2015 Tewelde Tesfaye 302

HIV replication cycle

2/3/2015 Tewelde Tesfaye 303

HIV---
 Disease
- AIDS
 Asymptomatic infection[mononucleosis like
symptoms] persistent generalized
lymphadenopathy  symptomatic AIDS
defining conditions
 Homozygous CCR5 mutation= immune to HIV
 Heterozygous CCR5 mutation= slow course
 The course of the illness follows the decline in
CD4+ T cells
 Long-term survivors may result when virus lacks a
functional nef protein

2/3/2015 Tewelde Tesfaye 304

 Course of HIV infection
 Typically spans about
a decade
 Stages include:
 Acute infection
[widespread
dissemination of HIV
& sharp decrease in
the number of CD4 T
cells]
 Clinical latency,
 AIDS, and
 Death.

2/3/2015 Tewelde Tesfaye 305

2/3/2015 Tewelde Tesfaye 306
 Clinical latency
 Asymptomatic HIV, or chronic HIV.
 Second stage of the natural history of HIV infection
 Can last from about three years to over 20 years
 Near the end of this stage:
- many people experience fever, weight loss,
gastrointestinal problems and muscle pains.
- 50-70% of people also develop persistent
generalized lymphadenopathy, characterized by
unexplained, non-painful enlargement of more
than one group of lymph nodes
 Although most HIV-1 infected individuals have a
detectable viral load and in the absence of
treatment will eventually progress to AIDS,
2/3/2015 Tewelde Tesfaye 307
 AIDS
 A late stage of HIV infection
 First described in 1981
 Since then, it has become a worldwide epidemic
 There is a decline in the number of CD4+ cells to
below 200/µl and an increase in the frequency of
opportunistic infections

2/3/2015 Tewelde Tesfaye 308

2/3/2015 Tewelde Tesfaye 309
 Conditions of early symptomatic period
 Bacillary angiomatosis (disseminated
Bartonellosis), Candidiasis (oral or persistent
vulvovaginal), Cervical dysplasia, or carcinoma
in situ
 Constitutional sx (fever 38.5 oc or persistent
diarrhea lasting > 1 month)
 Hairy leukoplakia
 Idiopathic thrombocytopenic purpura
 Listeriosis
 Pelvic inflammatory disease
 Peripheral neuropathy
2/3/2015 Tewelde Tesfaye 310
 Conditions associated with AIDS
 Encephalopathy, HIV-related
 Pneumonia, recurrent(leading cause of death)
 Fungal infections
- Candidiasis of the esophagus, bronchi, trachea, or
lungs
- Coccidioidomycoses, disseminated or
extrapulmonary
- Cryptococcus [leading cause of meingitis in AIDS
patients], extrapulmonary
- Histoplasmosis, disemianted or extrapulmonary
- Pneumocystis jiroveci pneumonia40%
2/3/2015 Tewelde Tesfaye 311
 Conditions associated with AIDS---
 Carcinomas
- Invasive cervical
- Kaposi’s sarcoma
- Burkitt lymphoma
- Immunoblastic or primary CNS lymphoma
 Viral infections
- CMV retinitis (with loss of vision) or disease (other than
liver, spleen, or nodes)
- HSV: chronic ulcers (>1month), bronchitis, pneumonitis,
or esophagitis
- Progressive multifocal leukoencephalophathy [JC virus]
- HIV Wasting syndrome [TNF-α]20%
2/3/2015 Tewelde Tesfaye 312
 Conditions associated with AIDS---
 Parasitic infections
- Cryptosporidosis, chronic intestinal (>1month)
- Isosporiasis, chronic intestinal (>1month)
- Toxoplasmosis of brain
 Bacterial infections
- Mycobacterium tuberculosis any site
(pulmonary or extrapulmonary)
- Mycobacterium avium complex or M. kansasii
disseminated or extrapulmonary
- Salmonella septicemia, recurrent
2/3/2015 Tewelde Tesfaye 313
2/3/2015 Tewelde Tesfaye 314
HIV Epidemiology
 Reservoir
-Human TH cells & macrophages
 Transmission: three main routes
1. Sexual contact: major mode of HIV transmission
[heterosexual contacts]
- In the US [2009], most sexual transmission occurred in men
who had sex with men [64% of all new cases]
2. Exposure to infected body fluids or tissues
- There is no risk of acquiring HIV if exposed to feces, nasal
secretions, saliva, sputum, sweat, tears, urine, or vomit
unless these are contaminated with blood.
- It is possible to be co-infected by more than one strain of
HIV [HIV superinfection]
3. Vertical transmission[Mother to child]: During pregnancy,
delivery, or breastfeeding
2/3/2015 Tewelde Tesfaye 315
 Average per act risk of getting HIV by exposure route to an infected
source
Exposure route Chance of infection
Blood transfusion 90%
Childbirth (to child) 25%
Needle-sharing injection drug use 0.67%
Percutaneous needle stick 0.30%
Receptive anal intercourse* 0.04-3.0%
Insertive anal intercourse* 0.03%
Receptive penile-vaginal intercourse* 0.05-0.30%
Insertive penile-vaginal intercourse* 0.01-0.38%
Receptive oral intercourse*§ 0-0.04%
Insertive oral intercourse*§ 0-0.005%
*assuming no condom use
§ source refers to oral intercourse performed on a man
2/3/2015 Tewelde Tesfaye 316
Epidemiology[HIV]

2/3/2015 Tewelde Tesfaye 317

2/3/2015 Tewelde Tesfaye 318
HIV/AIDS in Ethiopia
• ..\..\hivaidsprevalenceestimate.pdf

2/3/2015 Tewelde Tesfaye 319

 Laboratory analysis for HIV
Purpose Test
Initial screening Serologic: ELISA or latex particle
agglutination look for P24
Confirmation Serologic: Western blot or IF
Detection of virus in blood (viral load) RT-PCR
Detection of HIV infection in newborns PCR
of HIV+ mothers (provirus)
Early marker of infection P24 [capsid protein]
Evaluate progression of disease CD4:CD8 T cell ratio with flowcytometry
2:1= N

2/3/2015 Tewelde Tesfaye 320

Recommended prophylactic regimens during HIV
infection
Disease agent Begin prophylaxis Discontinue prophylaxis

Pneumocystis jiroveci <200 CD4 >200 for 3-6 months

Toxoplasma gondi <100 CD4 >100 for 3-6 months

Histoplasma capsulatum <100 CD4 Continue

(endemic area)
Mycobacterium avium <50 CD4 >100 for 3-6 months
intracellulare
CMV <50 CD4 >150 for 3-6 months
Cryptococcus neoformans <50 CD4 Continue

2/3/2015 Tewelde Tesfaye 321

 HIV: Treatment
Mechanism Name Resistance
RT inhibitors, Nucleoside End in “ine” Common, leads to cross-
or non-nucleoside resistance
analogs
Protease inhibitors End in “inavir” Common via protease
mutations, leads to cross-
resistance
HAART[combination] 2 nucleoside analogs and Increasing
therapy 1 protease inhibitor
Fusion inhibitors; CCR5 Fuzeon, enfuvirtide; Not yet
co-receptor antagonist; maraviroc; Raltegravir
integrase inhibitor  1st
drug of choice for HAART
therapy

2/3/2015 Tewelde Tesfaye 322

 HIV/AIDS prevention and control
 No vaccine is available and several are under trial
 However, vaccine production to HIV is difficult due to:
 Rapid mutation of the virus
 Absence of an appropriate animal model and
 Unclear understanding of which host immune responses are
protective
 Prevention consists of taking measures to avoid exposure to
the virus (sex education, not sharing needles, screening
donated blood for HIV)
 Post-exposure chemoprophylaxis after a needle stick injury by
azidothymidine (AZT), lamivudine and a protease inhibitor for
2-4 weeks prevents infection
 Screening pregnant mothers for HIV and those infected should
receive AZT or nevirapine during pregnancy
 Delivery by cesarean section is recommended
 Infected mothers should not breast feed their infants
2/3/2015 Tewelde Tesfaye 323
 HIV prevention---
 Education= probably the best
 Blood/organ screening
 Infection control
 Vaccine development (currently none available)

2/3/2015 Tewelde Tesfaye 324

 Oncogenic Viruses
 Viruses that cause or give rise to tumors.
 20% of human cancers believed to be of viral
origin and this may grow in the future [WHO
2002 report].

325
Major viral cancers
- Cervical cancer
- Burkitt’s lymphoma
- Hepatocellular carcinoma
- Kaposi’s sarcoma

326
Prevalence around the globe

327
328
 Oncogenic Viruses---
Virus % Associated cancer types
Hepatitis viruses [HBV,
4.9 Hepatocellular carcinoma [liver cancer]
HCV]
HTLV-1: Adult T-cell leukemia, Sezary T-cell
HTLV 0.03
leukemia, HTLV-2: Hairy cell leukemia
Cervical Cancer, Squamous cell anal carcinoma,
HPV 5.2 Penile cancer, oropharyngeal cancers, Cancers
of vulva/vagina, and cancer.

Kaposi’s sarcoma, multicentric Castleman's disease

KSHV(HHV-8) 0.9
and primary effusion lymphoma

Merkel cell
NA Merkel cell carcinoma
polyomavirus

Burkitt’s lymphoma, Hodgkin’s lymphoma, Post-

EBV NA transplant lymphoproliferative disease and
Nasopharyngeal carcinoma.
329
How do Viruses contribute to cancer?

 Integrations that cause activation or

inactivation of oncogenes or tumor suppressors
(e.g. RNA viruses)

 Expression of genes that alter key signal

transduction pathways
 Chronic activation of inflammatory
responses:

330
 How virus causes Cancers?
Mechanisms of viral oncogenesis
 Malignant transformation
- When a virus infects a cell, it expresses proteins that
cause the cell to proliferate and/or block apoptosis
 Provirus
 Proto-oncogene  “Mutation”  Oncogene
 Tumor Suppressor Genes
 Oncogenes:
- Promote cell proliferation
- Dominant & highly conserved
- Two types [Cellular, Viral]
331
 Major concept of tumorigenesis
 Mutation of an oncogene or tumor suppressor
gene
 Dosage effects:
- Oncogenes in amplified DNA
- Translocation (Burkitt’s Lymphoma)
- Provirus insertional mutagenesis
- Oncogene capture by retroviruse
- Interaction between oncogenes and tumor
suppressor genes- E6 & E7 of HPV combine
with & inactivate p53 & p110(Rb)
332
Viral oncogenes
 Responsible for oncogenesis resulting from persistent virus
infection.
 Target similar sets of cellular tumor suppressors or signal pathways
to immortalize and/or transform infected cells.
 Expression of the viral E6 and E7 oncogenes in papillomavirus, E1A
and E1B oncogenes in adenovirus, large T and small t antigen in
polyomavirus, and Tax oncogene in HTLV-1 are regulated by
alternative RNA splicing.
 However, this regulation is only partially understood.
 DNA tumor viruses also encode noncoding RNAs, including viral
microRNAs, that disturb normal cell functions.
 Among the determined viral microRNA precursors, EBV encodes 25
from two major clusters (BART and BHRF1), KSHV encodes 12 from a
latent region, human polyomavirus MCV produce only one
microRNA from the late region antisense to early transcripts, but
HPVs appears to produce no viral microRNAs. 333
 DNA Tumor Viruses
Virus Viral Oncoproteins Cellular Targets

Large T antigen p53 and pRb tumor suppressor genes

Polyomavirus SV40
Small t antigen PP2A

E6 p53, DLG, MAGI-1, MUPP1

HPV
E7 pRb

Bovine
E5 PDGFβ receptor
papillomavirus

E1A pRb
Adenovirus
E1B-55k p53

Adenovirus 9 E4ORF1 DLG, MAGI-1, MUPP1

LMP1 TRAFs
EBV vIL10 IL-10 receptor (soluble viral cytokine)
BCL2 homolog Rescues cell from apoptosis
334
335
 CANCER CELLS AND NORMAL CELLS
CANCER CELLS NORMAL CELLS
Frequent
mitoses

Normal
cell

Nucleus

Few
Blood vessel mitoses

Abnormal
heterogeneous cells

Loss of contact inhibition Oncogene expression is rare

Increase in growth factor secretion Intermittent or co-ordinated
Increase in oncogene expression growth factor secretion

Loss of tumor suppressor genes Presence of tumor suppressor

genes
336
 Human adenoviruses
 Small DNA viruses that commonly cause
respiratory infections.
 Have not been linked to any human cancer, but
some serotypes, such as adenovirus types 2, 5,
12, 18, and 31, are capable of transforming
rodent cells in culture and inducing tumors in
hamsters or rats.
 Two viral oncogenes, E1A and E1B, have been
identified as responsible for the adenovirus
tumorigenicity

337
HPV
51 types identified - most common are types 6 and 11
 Most cervical, vulvar and penile cancers are ASSOCIATED with types 16 and 18 (70% of
penile cancers)

Urogenital cancer
wart malignant squamous cell carcinoma

Squamous cell carcinoma:

Larynx
Esophagus All histologically similar
Lung
10% of human cancers may be HPV-linked??
338
HPV
Both the Rb protein and the p53
proteins [Tumor suppressor genes or
anti-oncogenes]
HPV [HVP-16 and HPV-18] synthesize
two proteins [E7 and E6].
E7 binds to the Rb protein preventing
it from binding to the host transcription
factor E2F.
E2F is now free to bind to the
promoters of genes (like c-myc) that
cause the cell to enter the cell cycle
(right).
The E6 binds the p53 targeting it for
destruction by proteasomes and thus
removing the block on the host cell's
entering the cell cycle. 339
 HPV-induced cancers

- HPVs are found in 91% of women with cervical cancer

340
HPV---

341
 Herpes Viruses
Considerable evidence for role in human cancer
• Some very tumorigenic in animals
• Viral DNA found in small proportion of tumor cells: “hit and run”

• Epstein-Barr Virus
• Burkitt’s Lymphoma
• Nasopharyngeal cancer
• Infectious mononucleosis
• Transforms human B-lymphocytes in vitro

342
 EBV
Pathologies in immuno-competent individuals
• Infectious mononucleosis
• African form Burkitt’s Lymphoma
• Hodgkin’s lymphoma
• Nasopharyngeal carcinoma (NPC)
Pathologies in immuno-compromised individuals
• Post-transplant lymphoproliferative diseases (PTLD)
• Hodgkin’s lymphoma
• A variety of non-Hodgkin’s lymphoblastic malignancies

343
Burkitt's lymphoma
 Burkitt's lymphoma in the tropics, where it is more
common in malaria-endemic regions [Malaria
serves as cofactor by causing immunosuppression]
- c-myc oncogene is translocated to region of Ab
synthesis
 Nasopharyngeal cancer, particularly in China and SE
Asia, where certain diets may act as co-carcinogens
 B cell lymphomas in immune suppressed
individuals (such as in organ transplantation or HIV)
 Hodgkin's lymphoma in which it has been detected
in a high percentage of cases (about 40% of
affected patients)
 X-linked lymphoproliferative Disease (Duncan's
syndrome)
344
EBV---
 EBV encodes a viral oncogene, LMP1 (latent membrane
protein-1 or BNLF1).
 LMP1 is expressed in EBV-associated lymphoma and is
essential for B-cell transformation and for disruption of
cellular signal transduction.
 Although the EBV nuclear antigen 1 (EBNA1) is one of
the earliest viral proteins expressed after infection and
is the only latent protein consistently expressed in viral-
associated tumors, recent results indicate that EBNA1 is
not a viral oncoprotein.
 BARF1 (BamHI-A reading frame-1) is also an early gene
but is expressed as a latent gene in most NPCs.
 Recent studies have suggested that BARF1 may have an
important role in NPC oncogenesis.
345
KSHV[HHV-8]

Kaposi’s sarcoma
Hematologic malignancies
• Primary effusion lymphoma
• Multicentric Castleman's disease (MCD) – a rare
lymphoproliferative disorder (AIDS)
• MCD-related immunoblastic/plasmablastic
lymphoma
• Various atypical lymphoproliferative disorders

Encodes a viral G protein-coupled receptor (vGPCR) that

presumably functions as a viral oncogene in immortalization of
human endothelial cells and induction of angioproliferative tumors.

346
 Human polyomaviruses
 Simian virus 40 (SV40), one of the most common latent viruses of
rhesus monkeys.
- Tumor antigens (T antigens) that can cause malignant cell
transformation.
 BK virus & JC virusoncogenic in rodents and nonhuman primates, but
thier roles in human cancer is not clear.
 Recently, a new human polyomavirus, Merkel cell polyomavirus (MCV),
was discovered in ~80% of Merkel cell carcinomas (MCCs).
- An established MCC cell line contains monoclonal MCV DNA
integration.
- The integrated MCV DNA encodes a mutant T antigen that prevents
autoactivation of integrated virus replication.
 Interestingly, MCV and two new human polyomaviruses, polyomavirus-
6 (HPyV6) and HPyV7, appear to inhabit healthy human skin with 40%
detection rate and approximately 88% of adult subjects without MCC
were MCV seropositive.

347
 Hepatitis B virus (HBV)
 HBV is endemic in Southeast Asia and sub-
Saharan Africa.
 Precise role of HBV in causing liver cancer is not
yet understood,
 Evidence suggests that the HBx gene could be a
viral oncogene, as its protein product can
disrupt signal transduction and deregulates cell
growth.
 HBx is not a split gene and thus there is no RNA
splicing in its expression.
348
 HTLV-1
 Adult T-cell leukemia/lymphoma is endemic in
the southern islands of Japan, the Caribbean
basin, and South Africa.
 Only about 1 percent of infected individuals will
develop leukemia, and then only after a period
of 20 to 30 years of asymptomatic infection.
 Although the mechanism of transformation is
not clear, the viral oncoprotein Tax, which
promotes transcription and cell cycle
progression, may be involved in setting up an
autocrine (self-stimulating) loop that causes
continuous proliferation of infected T cells
349
Hepatitis C virus (HCV)
 Although HCV oncogenesis is not well
understood, persistent HCV infection is a
prerequisite for the development of HCV-
associated liver cancer.
 There are no oncogenes in the viral genome,
but liver-specific miR-122 is required for HCV
replication

350
 Prions & Slow virus diseases
 Prions are proteinacious infectious agent
 A slow virus is a virus associated with a disease
having a long IPD (months to years) but
irreversibly and terminate in a severe
compromised state or death.
 Prions---
Disease Infectious Host Comments
agent

Kuru Prion Human Sub-acute spongiform encephalopathy

(SSE), Fore Tribe, New Guinea,
Cannibalism
Creudtzfeldt- Prion Human SSE, Genetic predisposition, ingestion of
Jakob cow brains [Mad cow disease], US

Gerstmann– prion Human SSE

Sträussler–
Scheinker
syndrome (GSS)
Scrapie Prion Sheep SSE, Scraping wool off on fences
 Prion disease presentation
 Vary from patient to patient.
 However, some general characteristics of prion
diseases:
 Cause diseases that are confined to the CNS
 Have a prolonged IPD
 Follow a slow, progressive, fatal course of disease
 Produce a spongiform encephalopathy
 Characteristically result in vacuolation of neurons
 Can cause formation of fibrillar aggregates, which
contain PrP and have amyloid-like characteristics
Prion disease---
Types of CJD
1)variant (vCJD): caused by the consumption of food
contaminated with prions, which also cause BSE.
2)sporadic (sCJD): accounts for 85% of cases of CJD.
3)familial (fCJD): accounts for the majority of the
other 15% cases of CJD.
4)iatrogenic: arises from contamination with tissue
from an infected person, usually as the result of a
medical procedure [blood transfusion from the
infected person, use of human-derived pituitary
growth hormones, gonadotropin hormone therapy,
corneal and/or meningeal transplants]
 Alzheimer Disease vs CJD
 There are some neuropathologic similarities
between CJD and Alzheimer disease, including
the appearance of amyloid plaques.
 However, the disease has not been transmitted
experimentally to primates or rodents, and the
amyloid material in the brains of Alzheimer
patients does not contain PrPSc protein.
Slow viruses
 Cause an asymptomatic primary infection
 Have a long incubation period ranging from
months to years
 Follow a slow but relentless progressive course
leading to death
 Tend to have a genetic predisposition
 Often re-emerge from latency if the host
becomes immuno-compromised
 Slow conventional viruses
Virus Disease

JC Virus Progressive multifocal leukoencephalopathy [PML]

BK Virus BK Nephropathy
Measles Subacute Sclerosing Panencephalitis [SSPE]

Rubella Progressive Rubella Panencephalitis

HIV AIDS Dementia

HTLV-1 Adult T-cell Leukemia/Lymphoma

HTLV -2 Atypical Hairy Cell Leukemia

Rabies Virus Rabies