EGERTON UNIVERSITY

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E-CAMPUS

ZOOL 143: Biology of HIV/AIDS and Society

Topic 5 Handout

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Topic Five: Transmission and Pathogenesis of HIV Particle

Introduction

Welcome to topic five. When a healthy person comes into contact with body fluid
of another person infected with HIV, the HIV particles enters the body and may
cause an infection. In this topic, we shall now learn about the various modes of
HIV transmission as well as the process of disease development (pathogenesis).
HIV particle destroys white blood cells which are crucial in maintaining the
function of the human immune system. As HIV multiplies and attacks more of
these cells, the immune system progressively weakens and the HIV-infected
person is less equipped to fight off infection and disease. But over time, HIV
levels increase in the blood while the number of CD4+ T cells decline.
Subsequently the immune system is unable to fight infections ultimately resulting
in the development of AIDS. Welcome to the discussion.

Learning Outcomes

By the end of this topic you should be able to:

i. Describe the various modes of HIV transmission.

ii. Describe routes of entry of HIV particle into the body.
iii. Describe the body’s cellular response to HIV infection
iv. Explain how HIV destroys host cells
v. Describe the HIV life cycle
vi. Describe the clinical course of HIV infection

5.1 Transmission of HIV-1

a) Body Fluids Carrying HIV Particles

HIV is transmitted only through the exchange of infected body fluids of infected
person with uninfected person. There is a significant risk of infection when these
body fluids are passed directly into another person's blood. HIV particles occur in
high concentrations in the following body fluids of infected individuals:

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 i. Blood,
ii. semen,
iii. vaginal secretions and
iv. cervical secretions
v. Breast milk

Although the virus occurs in saliva, tears, cerebrospinal fluid, and urine, these
fluids do not pose a significant risk because of the low concentration of the virus
and the absence of a common mechanism for them to enter the blood of another
person. There is no risk of infection through social non-sexual contact such as
kissing, sharing utensils, body contact, use of public toilets or through mosquitoes
or other insects.

b) Modes of HIV Transmission

There are only three modes of transmission for HIV:

i) Blood and Blood Products

Each donor must sign a declaration stating that she or he does not have any high
risk factors for HIV. Blood transmission of HIV is virtually confined to needle
and syringe sharing among injecting drug users.

ii) Mother-to-Child Transmission (MTCT)

Approximately 30% of infants born to untreated HIV-positive women are

infected. It is not known at what stage of the pregnancy the foetus is infected, but
recent evidence supports the notion that the infant often becomes infected during
the birth process.

iii) Sexual Activity

Exact levels of risk for the various forms of sexual activity are not known, but
some sexual practices have higher risks associated with them than others.
Transmission can occur in either direction during unprotected vaginal intercourse.
HIV can be absorbed into the woman's bloodstream during unprotected vaginal
intercourse via tears in the vaginal wall, genital ulceration, or by absorption
through the membrane of the cervical canal. Anal intercourse without a condom is

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the highest risk sexual activity because the rectal lining is fragile and prone to
tearing, thus allowing easy access for infected blood and semen.

c) Viral Shedding

Virus shedding is the release of virions in an area of the body that enables them to
spread from one person to another. The major sites of viral shedding are:

• Genital tract in semen and vaginal secretions.

• Respiratory tract in mucus and saliva, however, saliva contains natural
inhibitors (e.g. IgA and proteolytic enzymes) which inactivate the virus.
• And intestinal and urinary tract in faeces and urine, however, feces and
urine usually leave the body.

d) Route of HIV-1 Entry

The most important route of entry into the body is the moist surface provided by
mucous membranes. Mucous membrane forms linings of moist surfaces of:

• genital and urinary systems,

• digestive tract (GIT) system,
• respiratory system
• the eyes (forms the conjunctiva which covers the eye ball and lines the
eye lids).

Mucous membrane consists of a thin layer of epithelial cells covered with a

blanket of mucus produced from the epithelial cells.It is protected by IgA and
underlying lymphoid organs.

5.2 Host Response to HIV Virulence

a) The Host Cellular Response to HIV

The probability of HIV infection depends on several factors:

• the life cycle of HIV strain,

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 • the host cellular environment,
• number of infective HIV virions in the body fluid in contact with the
host.
• the number of cells available at the site of contact that have appropriate
CD4 receptors.

The ability of HIV to select specific cell types during infection is termed viral
tropism. Cells susceptible to HIV infection have special cell membrane proteins
called CD4 receptors. These cells include:

• blood monocytes and tissue macrophages

• T and B lymphocytes,
• natural killer (NK) cells,
• dendritic cells (in kidneys and lymph nodes),
• hematopoietic stem cells,
• endothelial cells,
• microglial cells (in the brain)
• gastrointestinal epithelial cells.

Macrophages are the first cells to be infected by HIV particle. Macrophages

engulf the HIV particles and display foreign antigen on the surface of their cell
membrane to alert helper T cells to the presence of pathogens. Helper T (TH) cells
are critical to coordinating the activity of the immune response by secreting
chemical messages (cytokines) which stimulate the non-specific immune response
to continue, and strengthen and boost appropriate specific responses. Helper T
cells have sometimes been called the "conductors" or the "generals" of the
immune system because they call up troops of B cells, cytotoxic T cells, and other
helper T cells to go into battle against invading pathogens.

In germinal centres (i.e. sites within secondary lymphoid organs where mature B
lymphocytes multiply), there is increased production of a variety of cytokines
such as tumor necrosis factor (TNF) and interleukine-6 (IL-6) which activate
CD4+ T lymphocytes and make them more susceptible to HIV infection. Other
types of cytokines with key roles in the regulation of normal immune function
may be secreted in decreased amounts during HIV infection. For example, CD4+
T cells lose their capacity to produce interleukin 2 (IL-2), a cytokine that enhances
the growth of other T cells and helps to stimulate other cells' response to invaders.
Once infected, CD4+ T cells may leave the germinal centers and infect other CD4+

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T cells that congregate in the region of the lymph node surrounding the germinal
center.

Because HIV preferentially infects a subset of T lymphocytes called helper T

(TH) cell, they become depleted in the patient. This can subvert and decimate the
immune system, leading to AIDS as HIV infection progresses. Macrophages then
serve as the source of HIV production when CD4+ T cells become depleted in the
patient.

5.3 Life cycle of HIV

Like all viruses, HIV is an intracellular pathogen hence cannot grow or reproduce
on its own. In order to make new copies of itself it must infect the cells of a living
organism. The process typically begins when a virus particle bumps into a cell that
carries on its surface a special protein called CD4.

The life cycle of HIV consists of 10 steps:

https://www.youtube.com/watch?v=8sipX86JfUw

Binding

• HIV comes into contact with a T-cell and binds to specific cellular proteins
that act as a viral receptor found on the membrane of that cell these
receptors normally function to communicate with other cells, but have been
exploited by HIV in order to initiate infection.
• The initial contact and binding to the cell occurs when the viral protein
gp120 binds to the cellular receptor CD4.

Fusion:

• Fusion between the viral and host cell membranes occurs when gp41 binds
to either CCR5 or CXCR4.

Infection stage

• Following binding and fusion, infection of the T-cell by HIV occurs.

• During this stage, the viral and cellular membranes ‘melt’ together and the
viral core is internalized.

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 • The nucleocapsid then breaks apart, releasing the viral RNA genome and
associated proteins, such as reverse transcriptase.

Reverse transcription:

• In order to successfully infect a cell, the viral genome must become

integrated into the host’s DNA.
• For this to happen, the single stranded RNA genome must be converted into
double stranded DNA. This process is called reverse transcription and is
performed by the enzyme reverse transcriptase.
• The word ‘reverse’ is used to indicate that in all life forms other than
retroviruses (‘backwards’ viruses) transcription is the process of converting
DNA to RNA. HIV, however, use reverse transcriptase to synthesize a
double stranded DNA copy using its RNA genome as a template. DNA to
RNA, instead of RNA to DNA like all other life forms.

Integration

• Once the double stranded DNA copy of the HIV genome has been produced
it must integrate into the host cell’s DNA in the nucleus.
• The viral enzyme integrase cuts the host DNA and pastes in the viral
information. The viral genes are now a permanent part of that cell’s DNA.
The only way to remove the viral is to destroy the infected cell.

Latent infection stage

• After the integration process is complete, the cell is latently infected with
HIV, which is now called a provirus.

Transcription and Translation

• If activated, the provirus begins transcription of RNA copies of its genes.

• Some of these copies are used to produce viral proteins that build the new
virus, while others serve as new viral genomes that will be packaged in
those viruses.

Assembly stage

• When viral proteins are produced they are connected to each other like
beads on a string.

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 • However, in order to function correctly and build the new viral capsid they
must be cut apart. This separation, or cleavage, is accomplished by the
protease enzyme.
• After separation occurs, the structural subunits of HIV mesh with the cell’s
membrane and begin to deform a section of the membrane. Through this
process, the nucleocapsid is formed and wound tightly inside.

Budding

• During budding, this nucleocapsid merges with the deformed cell

membrane to form the viral envelope.

Release and maturation

• The newly created viral particle is releases from the cell, taking with it a
piece of the cellular membrane that how has gp120 and gp41 inserted into
it.
• The virus finishes protease processing of structural proteins and is ready to
infect another cell.

N/B

• This entire process take about 14hours and millions of new viruses are
produced every day.
• ‘Viral load’ is a measurement of the rate of virus production and indicates
how actively HIV is being produced.
• After being used as a factory for making new viruses for a period of time,
the T-cells that have been hijacked by HIV eventually do die.
• As more T cells die, the immune system becomes less capable of
responding effectively to disease.
• One definition of AIDS is having less than 200 T cells per milliliter of
blood, even if the person is symptom free. This person now has no defenses
against opportunistic diseases. As the viral load in an individual increase,
their T cell count decreases. Close monitoring of both T – cell count and
viral load enables doctors to determine the best time for initiating ant-
retroviral treatment.

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Figure 5.1: The HIV-1 life cycle (Source: Hoffmann and Rockstroh, 2012)

5.4 How HIV Particle Destroys Host Cells

There are several theories of how HIV may destroy or disable CD4+ T cells in an
HIV infected individual, eventually overwhelming the immune system's
regenerative capacity:

i) Direct cell killing. Infected CD4+ T cells may be killed directly

when large amounts of virus are produced and bud off from the
cell surface, disrupting the cell membrane, or when viral proteins
and nucleic acids collect inside the cell, interfering with cellular
machinery.
ii) Syncytia formation. Infected cells also may fuse with nearby
uninfected cells through CD4-mediated fusion, forming balloon-
like giant cells called syncytia. This mechanism of cell-to-cell
spread of HIV has been associated with the death of uninfected
cells. The presence of syncytia-inducing variants of HIV has been
correlated with rapid disease progression in HIV-infected
individuals.
iii) Apoptosis. Infected CD4+ T cells may be killed when cellular
regulation is distorted by HIV proteins, probably leading to their
suicide by a process known as programmed cell death or

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 apoptosis. Uninfected cells also may undergo apoptosis.
Investigators have shown in cell cultures that the HIV envelope
alone or bound to antibodies sends an inappropriate signal to
CD8+ T cells causing them to undergo apoptosis even though not
infected by HIV.
iv) Innocent bystanders. Uninfected cells may die in an innocent
bystander scenario: HIV particles may bind to the cell surface,
giving them the appearance of an infected cell and marking them
for destruction by killer T cells.

5.5 Clinical Course (Stages) of HIV Infection

HIV infection has basically four stages: incubation period, acute infection, latency
stage and AIDS (Fig. 5.2).

a) Primary Infection Period

The initial incubation period upon infection is asymptomatic and usually lasts
between two and four weeks. The initial infection with HIV generally occurs after
transfer of body fluids from an infected person to an uninfected one.

Figure 5.2: Typical course of HIV infection (Source: Elgert, 2009)

Key: Blue = CD4 T cell count (cells per µL); Red = HIV RNA copies per mL of
plasma

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b) Acute Infection

Primary HIV infection is followed by a burst of viremia in which virus is easily

detected in peripheral blood in mononuclear cells and plasma. Two to four weeks
(28 days) after exposure to the virus, up to 70 percent of HIV-infected persons
suffer flu-like symptoms such as fever, lymphadenopathy (swollen lymph nodes),
pharyngitis (sore throat), rash, myalgia (muscle pain), malaise, and mouth and
esophageal sores. The number of CD4+ T cells in the bloodstream decreases by 20
to 40 percent (the normal blood value is 1200 cells per µL).

This acute viremia is associated with the activation of CD8+ T cells, which kill
HIV-infected cells, and subsequently with antibody production, or
seroconversion. The CD8+ T cell response is thought to be important in
controlling virus levels, which peak and then decline, leading to clinical latency
period.

Antibodies to HIV usually develop within 2 to 8 weeks, and almost always by 12

weeks. The 12 weeks after initial infection is called the "window period", where
a negative test does not necessarily indicate that a person is free of the virus and a
follow-up test will be necessary. However, by the end of the window period
virtually all infected people will have a positive blood test (i.e. they will test
"seropositive" or "HIV-positive"). Developing an HIV-positive test is known as
"seroconversion".

c) Latency Period

The burst is followed by replication at a lower level when, the patient's immune
system fights back to dramatically reduce HIV levels with killer T cells (CD8+ T
cells), which attack and kill infected cells that are producing virus, and B-cell-
produced antibodies. A patient's CD4+ T cell count may rebound to 80 to 90
percent of its original level. A person then may remain free of HIV-related
symptoms, often for between two weeks to twenty years, despite a smoldering
low-level replication of HIV in the lymphoid organs and latent, ongoing immune
system destruction.

During this early phase of infection, HIV is active within lymphoid organs, where
large amounts of virus become trapped in the follicular dendritic cells (FDC)
network. The surrounding tissues that are rich in CD4+ T cells may also become

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infected, and viral particles accumulate both in infected cells and as free virus.
Individuals who are in this phase are still infectious. During the latency period,
enough of the immune system remains sufficiently intact to provide immune
surveillance and to prevent most infections.

Since HIV provirus becomes part of the infected host's cellular DNA, the host
cells may be infectious even if there are detectable HIV antibodies or if no virus
can be measured in the patient's serum. In addition, HIV can mutate very easily;
the HIV reverse transcriptase enzyme makes many mistakes while making DNA
copies from HIV RNA. As a consequence, many variants of HIV develop in an
individual (known as antigenic variation), some of which may escape immune
attack by antibodies or killer T cells. Due to antigenic variation, antibodies formed
against HIV are not protective and an infective state can persist despite the
presence of even high antibody titters. Chronic immune system activation during
HIV disease may also result in a massive stimulation of a person's B cells,
impairing the ability of these cells to make antibodies against other pathogens.

d) AIDS Stage

A person is said to have AIDS if he/she is HIV+ve and has at least one AIDS-
defining condition and or a CD4 cell count of 200 cells or less (NB: Normal CD4
cell count ranges between 500-1500cell/mL). The HIV-infected person may live
up to an average of 8 or 10 years after initial infection and before development of
the clinical symptoms of AIDS. The final phase of HIV infection occurs when a
significant number of CD4 lymphocytes have been destroyed and when
production of new ones cannot match destruction. When CD4+ T cell numbers
decline below a critical level of 200 cells per µL, cell-mediated immunity is lost,
marking the appearance of clinical AIDS.

The first symptoms often include moderate and unexplained weight loss, recurring
respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis),
prostatitis, skin rashes, and oral ulcerations. These opportunistic infections are
caused by microbes that usually do not cause illness in healthy people (Table 5.1);
infections are often severe and sometimes fatal because the immune system is so
ravaged by HIV that the body cannot fight them.

HIV disease is not uniformly expressed in all individuals. A small proportion of

infected individuals develop AIDS and die within months following primary
infection, 90% are likely to die within 2 years if not treated, while approximately

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5% of HIV infected individuals exhibit no signs of disease even after 12 or more
years. The latter are called "long term non-progressors".

Topic Summary

In this topic, we have discussed how HIV particle is transmitted and how it causes
HIV/AIDS disease. We have learned that:

• HIV is transmitted only through the exchange of infected body fluids

between infected person and uninfected person. HIV particles occur in high
concentrations in breast milk, blood, semen, and vaginal secretions and
cervical secretions. There are only three modes of HIV transmission:
through infected blood or blood products, sexual activity or, mother-to-
child.
• The major sites of viral shedding are genital tract, respiratory tract,
intestinal and urinary tract. These are moist surface provided by mucous
membranes and serve as important route of entry into the body.

• The probability of HIV infection depends on several factors, one of which

is presence of cells with CD4 receptors. The HIV life cycle begins when it
bumps into a CD4 cell and goes through binding and fusion, reverse
transcription, integration, transcription assembly and finally budding. The
new HIV virions move on to infect other cells while killing them. HIV
particles kill CD4 T cells by direct cell killing, syncytia formation,
apoptosis and innocent bystander mechanisms.

• Macrophages, the first CD4 cells to be infected, engulf the HIV particles
and display foreign antigen on the surface of their cell membrane to alert
helper T cells to the presence of pathogens. The helper T cells stimulate the
non-specific immune response and strengthen and boost appropriate
specific responses.

• Because HIV preferentially infects helper T cell, they become depleted in

the patient, which subvert and decimate the immune system, leading to
AIDS.

• Clinically, the course of HIV infection has four stages:

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• Primary infection stage– asymptomatic, lasts between 2-4 weeks.

• Acute infection stage -A burst of viremia, lasts for 2-4 weeks, show flu-like
symptoms.

• Latency stage – Asymptomatic, CD4 cell count slightly increases, viral load
falls, HIV antibodies appear, has long period.

• AIDS stage – CD4 cell count drops, OIs emerge.

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