Viruses are the smallest infectious agents (20-300 nanometers) Possess only one kind of nucleic acid, either DNA or RNA as their genome Capable of replication only within living cells (genetic parasites)


Viral Structure


General Structure of Viruses

Size range –
– most <0.2 μm; requires electron microscope

Virion – fully formed virus able to establish an infection

Prions - misfolded proteins, contain no nucleic acid
– cause transmissible spongiform encephalopathies – fatal neurodegenerative diseases – common in animals:
   

scrapie in sheep & goats bovine spongiform encephalopathies (BSE), aka mad cow disease wasting disease humans – Creutzfeldt-Jakob Syndrome (CJS)

Extremely resistant to usual sterilization techniques


Other noncellular infectious agents

Satellite viruses – dependent on other viruses for replication
– adeno-associated virus – replicate only in cells infected with adenovirus – delta agent – naked strand of RNA expressed only in the presence of hepatitis B virus

Viroids - short pieces of RNA, no protein coat; only been identified in plants, so far

Viral Structure: Covering

– Protects the nuclear material – Responsible for introduction of viral nucleic acid into a suitable host cell – Stimulates the immune system

Viral Structure: Covering - CAPSID

CAPSID: The outer protective shell
– The most prominent geometric feature – Composed of identical protein subunits – CAPSOMERS – Formed by spontaneous self-assembly of capsomers

Viral Structure: Naked Viruses

Viral Structure: Covering - ENVELOPE
Formed when the viral particle carries off a part of the host cell’s membrane (any part of the endomembrane system may be used)  SPIKES or PEPLOMERS

– Protein spikes protruding through the envelope from the capsid – Essential for attachment to the next host

Viral Structure: Enveloped Viruses

Genetic material of the particle  Viruses may contain either DNA or RNA BUT NOT BOTH  DNA or RNA may exist as single or doublestranded

Viral Structure: Central Core – Nucleic Acids

Viral Morphology
Helical Icosahedral

Viral Morphology
Enveloped Complex

Modes of Viral Multiplication
     

Adsorption - binding of virus to specific molecule on host cell Penetration - genome enters host cell Uncoating – the viral nucleic acid is released from the capsid Synthesis – viral components are produced Assembly – new viral particles are constructed Release – assembled viruses are released by budding (exocytosis) or cell lysis


budding – exocytosis; nucleocapsid binds to membrane which pinches off and sheds the viruses gradually; cell is not immediately destroyed  lysis – nonenveloped and complex viruses released when cell dies and ruptures  Number of viruses released is variable

– 3,000-4,000 released by poxvirus – >100,000 released by poliovirus

Cytopathic effects - virus-induced damage to cells
      

Changes in size & shape Cytoplasmic inclusion bodies Nuclear inclusion bodies Cells fuse to form multinucleated cells. Cell lysis Alter DNA Transform cells into cancerous cells


Persistent Infections
Persistent infections - cell harbors the virus and is not immediately lysed  Can last weeks or host’s lifetime; several can periodically reactivate – chronic latent state

– measles virus – may remain hidden in brain cells for many years – herpes simplex virus – cold sores and genital herpes – herpes zoster virus – chickenpox and shingles


Some animal viruses enter host cell and permanently alter its genetic material resulting in cancer – transformation of the cell. Transformed cells have increased rate of growth, alterations in chromosomes, and capacity to divide for indefinite time periods resulting in tumors. Mammalian viruses capable of initiating tumors are called oncoviruses. – Papillomavirus – cervical cancer – Epstein-Barr virus – Burkitt’s lymphoma


Lysogeny results in the spread of the virus without killing the host cell.  Phage genes in the bacterial chromosome can cause the production of toxins or enzymes that cause pathology – lysogenic conversion.

– Corynebacterium diphtheriae – Vibrio cholerae – Clostridium botulinum


Modes of entry

    

Respiratory tract though inhalation Gastrointestinal tract Skin Sexual Direct contact Transfusion of blood

Effects of virus on the host cell
 

 

CPE or cellular effect Transformation of normal cell to malignant cell Latent infection Clumping of RBC

Some of the Medically Important Viruses
Family Genus Common Name of Genus Members Disease

DNA Viruses Herpesviridae Simplexvirus Herpes simplex Cold sores, 1&2 virus genital herpes Varicella zoster Chicken pox virus Adenoviridae Mastadenoviru Human s adenovirus Colds, URI

Papovaviridae Papillomavirus Human Warts papillomavirus (HPV)

Some of the Medically Important Viruses
Family Genus Common Name of Genus Members RNA Viruses Picornaviridae Enterovirus Hepatovirus Rhinovirus Togaviridae Flaviviridae Filoviridae Alphavirus Flavivirus Filovirus Poliovirus



Hepatitis A virus Short-term hepatitis Human rhinovirus Rubella virus Dengue fever virus Ebola virus Common colds German measles Dengue fever Ebola fever


– Entero virus

Arbo virus
– Alpha – Flavi virus

Myxo virus
– – – Paramyxovirus Orthomyxovirus pseudomyxovirus

Rhabdo virus

Picorna virus
– Smallest RNA virus – Single strand RNA


 

Coxsackie virus Enteric human pathogenic orphan


 

 

Paralysis or poliomyelitis Septic meningitis with no paralysis OPV Salk vaccine

Polio virus


Dengue virus
      

Dengue fever Breakbone fever JBE Yellow fever virus Chikungunya virus West Nile fever virus Murray valley encephalitis virus

Myxo virus

– Mumps virus – Endemic parotitis



    

Virus related to Measles virus MAN ONLY HOST ONE SEROTYPE SUB-CLINICAL INFECTIONS CONTAGIOUS BEFORE AND AFTER SYMPTOMS Affects the Parotid glands (Viral Parotitis) and may cause orchitis that may lead to infertility

– LIVE ATTENUATED VACCINE – DOES NOT SPREAD TO CONTACTS – Contradindicated in  immunesuppressed  pregnant women

– – – – Parainfluenza virus Respiratory syncitial virus Rhinovirus coronavirus


Severe Acute Respiratory SyndromeAssociated Coronavirus (SARS)
Newly emerging disease – 2002  Transmitted through droplet or direct contact  Fever, body aches, and malaise  May or may not experience respiratory symptoms with breathing problems; severe cases can result in respiratory distress and death  Diagnosis relies on exclusion of other likely agents.  Treatment is supportive.



Influenza Virus


– Measles – Koplick’s spots ( oral lesion ) – SSPE

– German measles – Transplacental



– Alphavirus genus – Rubivirus genus


– mild

– can be severe

Two clinical forms:  Postnatal rubella – malaise, fever, sore throat, lymphadenopathy, rash, generally mild, lasting about 3 days  Congenital rubella – infection during 1st trimester most likely to induce miscarriage or multiple defects such as cardiac abnormalities, ocular lesions, deafness, mental and physical retardation  Diagnosis based on serological testing  No specific treatment available  Attenuated viral vaccine MMR

  

SORE THROAT, RUNNY NOSE, COUGH FEVER RASH, MINOR, IRREGULAR – lasts 12hour to 5days – not always seen ARTHRALGIA, ARTHRITIS – especially in adults, especially women LYMPHOADENOPATHY



 thrombocytopenia  hepatomegaly  splenomegaly  intrauterine

growth retardation  bone lesions  pneumonitis






Transplacental effect
      

Possible chromosomal breakage Inhibition of normal mitosis Deafness Congenital heart disease Cerebral damage Mental retardation Occasionally glaucoma



 

Rabies Human vaccine
– Human diploid cell – DEV- Duck’s embryo vaccine

Animal vaccine
– Flurry stain – Street Alabama dufferin strain

 

Heller stain Negri bodies

 Virus

enters through bite, grows at trauma site for a week and multiplies, then enters nerve endings and advances toward the ganglia, spinal cord and brain.  Infection cycle completed when virus replicates in the salivary glands


Clinical phases of rabies:

  

Prodromal phase – fever, nausea, vomiting, headache, fatigue; some experience pain, burning, tingling sensations at site of wound Furious phase – agitation, disorientation, seizures, twitching, hydrophobia Dumb phase – paralyzed, disoriented, stuporous Progress to coma phase, resulting in death



    

Adenovirus Pox virus Herpes virus Human papova virus Hepatitis virus

    

Tonsilitis Adenitis Mild respiratory illness Coryza cough


Pox virus
 

Small pox ( variola major ) Alastrim ( variola minor )


Herpes virus

Herpes simple type A
– Gingivomastitis – Vesicular eruption of the membrane of oral cavity

Herpes simplex type B
– Vulvovaginitis – Danger of congenital complication ( liver, CNS)

Genital Herpes Transmission
 

Major routes: sexual & mother-to-infant Most sexual transmission probably occurs when index case is asymptomatic Efficiency of transmission is greater from men to women than women to men
u u u

Mertz, et al: 144 serodiscordant couples Almost 17% man-to-woman transmission Almost 4% woman-to-man transmission

Male Herpes

Female Herpes

Genital Herpes Condom Effectiveness
 Latex

condoms, when used consistently and correctly, are highly effective for:

 And

can reduce the risk of:

– GC, CT, and Trichomonas – Genital herpes, syphilis, chancroid, and HPV, only when the infected areas are covered by the condom
CDC, 2002



Genital Herpes (HSV)
 

Transmission: skin to skin Symptoms: Prodrome--tingling in legs, buttocks or groin Lesion--itching, blister at infection site; Recurrences vary in frequency and severity Time to onset: 2-20 days Pregnancy: 5% transmission when lesions present Diagnosis: culture, antibody test Treatment: symptom relief; antivirals effective

   

Herpes of the Newborn
 HSV-1

and HSV-2  Potentially fatal in the neonate and fetus  Infant contaminated by mother before or during birth; hand transmission by mother to infant  Infection of mouth, skin, eyes, CNS  Preventative screening of pregnant women; delivery by C-section if outbreak at the time of birth


– Virus of chicken pox – Might lead pneumonitis and encephalitis – Herpes zoster



– – – – – Inclusion mononucleosis Liver, kidney and lungs Associated with mild hepatitis Recognized in congenital condition Oncogenic potential


– – – – Infectious mononucleosis Agent of Burkitt’s lymphoma Nasopharyngeal carcinoma Oncogenic virus



Papilloma virus
– Verruca vulgaris – Condylomata acuminata

Polyoma virus
– JV virus ( progressive multifocal leucoencephalopathy ) – BK virus ( kidney transplant, chronic disease )

Papilloma virus

Verruca vulgaris

Condylomata acuminata

Typical Genital Warts

DOIA Website, 2000

Male HPV infection

Female HPV

Polyoma virus

The ABC’s of Hepatitis

US&A (v. 2/07)


HBV - Hepatitis B HBV Transmission

Unprotected sex with multiple partners Sharing needles during injecting drug use From infected mother to child during birth Sharps/needle sticks

HBV Cannot be Spread by:
Sneezing or coughing  Kissing or hugging  Breast feeding  Food or water  Sharing eating utensils or drinking glasses  Casual contact

US&A (v. 2/07)


 Hepatitis

B virus (HBV) is 100 more infectious than HIV  About 5% of Americans have been infected with HBV at some point during their lifetime  People who get infected with HBV can also get infected with Hepatitis D virus (HDV). If this happens, people often become very sick
US&A (v. 2/07)

Hepatitis B

HCV - Hepatitis C
Clinical Features

Incubation period No sign or symptoms

Average 6-7 weeks Range 2-26 weeks 80%

Acute illness (jaundice) ≤ 20% (Mild) Chronic infection Age- 75%-85% related 10%-70% (most are Chronic liver disease asymptomatic) Deaths from chronic liver 1%-5% disease Immunity No protection from future infection identified

HCV - Hepatitis C Symptoms
• flu-like symptoms • jaundice • fatigue • dark urine • abdominal pain • loss of appetite • nausea

HCV Transmission

• Injecting drug use • Hemodialysis (long-term) • Blood transfusion and/or

organ transplant before 1992 child during birth blood - mostly needlesticks

• From infected mother to • Occupational exposure to

• Sexual or household

exposures - rare

Sources of Infection -Hepatitis C

US&A (v. 2/07)


Hepatitis C

Risk Factors: – Long-term kidney dialysis – Sex with multiple partners – Tattooing or body piercing with shared needles or unsterilized equipment – Intranasal cocaine use with shared straws

Pamela Anderson claims her infection came from a tattoo needle

Etiology of HIV

HTLV-III- Human T cell Lymphotrophic virus III LAV- lymphadenopathyassociated virus * contains single RNA strand and a DNA synthesizing enzyme called reverse transcriptase

Causative Agent
 Retrovirus,

genus Lentivirus  Encode reverse transcriptase enzyme which makes a double stranded DNA from the single-stranded RNA genome  Viral genes permanently integrated into host DNA  Human Immunodeficiency Virus (HIV) the cause of Acquired Immunodeficiency Syndrome (AIDS)


HIV-1 and HIV-2  T-cell lymphotropic viruses I and II – leukemia and lymphoma  HIV can only infect host cells that have the required CD4 marker plus a coreceptor.

 

Th- T- helper MCH- major histocompatibility complex CTL- cytotoxic T cell

Cells of the immune system ( review )

B- cells
– Plasma cells – Memory cells

T- cells
Helper T cells (effector T cells or Th cells) are the "middlemen" of the adaptive immune system. Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the immune response. Depending on the size, cytokine signals received, these cells differentiate into TH1, TH2, TH3, TH17, THF, or one of other subsets, which secrete different cytokines. CD4+ cells are associated with MHC class II.

About T-helper

T helper cells (also known as effector T cells or Th cells) are a sub-group of lymphocytes (a type of white blood cell or leukocyte) that play an important role in establishing and maximizing the capabilities of the immune system.

they have no cytotoxic or phagocytic activity; they cannot kill infected host (also known as somatic) cells or pathogens, Th cells are involved in activating and directing other immune cells, and are particularly important in the immune system

Mature Th cells are believed to always express the surface protein CD4. T cells expressing CD4 are also known as CD4+ T cells.

Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+ T cells (associated with MHC class I), since they express the CD8 glycoprotein at their surface. Through SLOB[ clarification needed] interaction with T regulatory CD4+CD25+FoxP3+ cells, these cells can be inactivated to a anergic state, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis.[1]

Memory T cells are a subset of antigen-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (TCM cells) and effector memory T cells (TEM cells). Memory cells may be either CD4+ or CD8+.

Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring Treg cells and the adaptive Treg cells. Naturally occurring Treg cells (also known as CD4+CD25+FoxP3+ Treg cells) arise in the thymus, whereas the adaptive Treg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring Treg cells can be distinguished from other T cells by the presence of an intracellular molecule called FoxP3. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease

Natural killer T cells (NKT cells) are a special kind of lymphocyte that bridges the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize peptide antigen presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both Th and Tc cells (i.e., cytokine production and release of cytolytic/cell killing molecules).

γδ T cells (gamma delta T cells) represent a small subset of T cells that possess a distinct T cell receptor (TCR) on their surface. A majority of T cells have a TCR composed of two glycoprotein chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells.

HIV and AIDS The Cellular Picture
CD4+ T4 helper cells In advanced disease: the loss of another cell type CD8+ cytotoxic killer cells Suggests an infectious agent
A virus But initially difficult to grow Rapidly kills cells on which it grows

of one cell type throughout the course of the d

A fall in the CD4+ cells always precedes diseas

AIDS • AIDS is currently defined as the Definition presence of one of 25 conditions
indicative of severe immunosuppression OR • HIV infection in an individual with a CD4+ cell count of <200 cells per cubic mm of blood • AIDS is therefore the end point of an infection that is continuous, progressive and pathogenic • With the prevalence of HIV in the developing world, HIV and its

The cellular and immunological picture The course of the disease
• High 1. Acute Infection virus titer • Mild symptoms • Fall in CD4+ cells but recovers • Rise in CD8+ cells but recovers • A high virus titer (up to 10 million viruses per ml blood) • Macrophages infected Macrophages bring HIV into the body if sexually transmitted

2. A strong immune response
Virus almost disappears from circulation • Good cytoxic T cell response • Soluble antibodies appear later against both surface and internal proteins • Most virus at this stage comes from recently activated (dividing) and infected CD4+ cells •

3. A latent state Latency of virus and of symptoms • Virus persists in extravascular tissues • Lymph node dendritic cells • Resting CD4+ memory cells (last a very long time - a very stable

• 10 billion HIV particles per day • Virus half life 5.7 hours • 100-10 million virions per ml blood (set point) • Small minority of T4 cells are infected • Virus found in lymph nodes


4. The beginning of disease

Massive loss of CD4+ cells • CD4+ cells are the targets of the virus • Cells that proliferate to respond to the virus are killed by it • Dendritic cells present antigen and virus to CD4 cells • Epitope variation allows more and more HIV to escape from immune response just as response wanes • Apoptosis of CD4+ cells

Advanced disease - AIDS
CD8+ cells destroy more CD4+ cells • CD4 cell loss means virus and infected cells no longer controlled • As CD4+ cells fall below 200 per cu mm virus titer rises rapidly and remaining immune response collapses • CD8+ cell number collapses • Opportunistic infections

Epidemiology of HIV Infections
 Transmission

occurs by direct and specific routes: mainly through sexual intercourse and transfer of blood or blood products; babies can be infected before or during birth, and from breast feeding.  HIV does not survive long outside of the body.


Men account for 70% of new infections. Anal sex provides an entrance for the virus. IV drug abusers can be HIV carriers; significant factor in spread to heterosexual population

Insert figure 25.14
HIV routes of infection


Pathogenesis and Virulence Factors of HIV

HIV enters through mucous membrane or skin and travels to dendritic phagocytes beneath the epithelium, multiplies and is shed. Virus is taken up and amplified by macrophages in the skin, lymph organs, bone marrow, and blood. HIV attaches to CD4 and coreceptor; HIV fuses with cell membrane.

Reverse transcriptase makes a DNA copy of RNA.  Viral DNA is integrated into host chromosome (provirus).  Can produce a lytic infection or remain latent

Inexorable decline of CD4+ T4 cells
Why do all of the T4 cells disappear ? At early stages of infection only 1 in 10,000 cells is infected Late 1 in Of great importance to therapeutic strategy 40

Virus destroys the cell as a result of budding

But few cells are infected: Early stage of infection 1:10,000 Late 1:40


Why do all T4 cells

Why do all T4 cells disappear? - 2
Infected CD4 cell Gp120 positive

Cells Fuse

But syncytia not common Most T4 cells are not HIV+

Killing of CD4 cells 2. Syncytium Formation

Uninfected CD4 cell Gp120 negative

Could “sweep up” uninfected cells

Cytotoxi c T cell

Why do all T4 cells disappea r?

BUT: Most cells are not infected

Killing of CD4 cells 3. Cytotoxic T cell-mediated lysis

Killing of CD4+ cells 4. Binding of free Gp120 to CD4 antigen makes uninfected T4 cell look like an infected cell Complementmediated lysis Could account for the loss of uninfected T4 cells

Why do all T4 cells disappear? Induction of apoptosis
CD8 cell
(no CD4 antigen)

gp120 chemokine



CXCR4 chemokin e receptor

G protein signal


Binding to CXCR4 results in expression of TNF-alpha

Binding to CXCR4 results in expression of TNF-alpha on the cell surface

Why do all T4 cells disappear? Induction of apoptosis
CD8 cell



CD8 T cell apoptotic bodies

Macrophages may be infected by two routes
gp1 20 CD 4

HIV gp120 binds to macrophage CD4 antigen Virus is opsonized by anti gp120 antibodies which bind to macrophage Fc receptors - an enhancing vaccine problem antibody

Fc recepto r Antigp120


Primary effects of HIV infection:
– extreme leukopenia – lymphocytes in particular – formation of giant T cells and other syncytia allowing the virus to spread directly from cell to cell – Infected macrophages release the virus in central nervous system, with toxic effect, inflammation.

Secondary effects of HIV:
– Destruction on CD4 lymphocytes allows for opportunistic infections and malignancies.


Signs and Symptoms of HIV Infections and AIDS
 Symptoms

of HIV are directly related to viral blood level and level of T cells.  Initial infection – mononucleosis-like symptoms that soon disappear  Asymptomatic phase 2-15 years (avg. 10)


Antibodies are detectable 8-16 weeks after infection.  HIV destroys the immune system.  When T4 cell levels fall below 200/µ L AIDS symptoms appear including fever, swollen lymph nodes, diarrhea, weight loss, neurological symptoms, opportunistic infections and cancers.

Diagnosis of HIV Infection
 Testing

based on detection of antibodies specific to the virus in serum or other fluids; done at 2 levels  Initial screening
– ELISA, latex agglutination and rapid antibody tests – rapid results but may result in false positives

Follow up with Western blot analysis to rule out false positives  False negatives can also occur; persons who may have been exposed should be tested a second time 3-6 months later.

Insert Table 25.A page 776
AIDS-defining illnesses


Preventing and Treating HIV
 No

vaccine available

– monogamous sexual relationships – condoms – universal precautions


No cure; therapies slow down the progress of the disease or diminish the symptoms
– inhibit viral enzymes: reverse transcriptase, protease, integrase – inhibit fusion – inhibit viral translation – highly active anti-retroviral therapy


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