Immune Responses to HIV Infection

Prof. Stephen Yao Gbedema

Dept. of Pharmaceutics
FPPS, CHS, KNUST
Kumasi

Pharm 366 1
 Innate & adaptive immunity
Vertebrate immune systems response to pathogens
through two interconnected systems:
• Innate immunity
• Adaptive immunity

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 The major cells of innate immunity
Big eaters/Always hungry

Antigen Presenting Cells (APCs)

Proteins eaten by APCs are broken down to small pieces (peptides), which are loaded on special receptors (MHCs) and transported to
the cell surface. Peptide+MHC complex can be recognized by a T cell and that interaction can lead to an adaptive immune response.

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Adaptive immune response

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HIV/AIDS
• The first cases of the acquired immune deficiency
syndrome (AIDS) were reported in 1981
• but cases of the disease had been occurring unrecognized
for at least 4 years before its identification.
• The disease is caused by HIV; characterized
• 1) by a susceptibility to infection with opportunistic pathogens or
• 2) by the occurrence of an aggressive form of Kaposi's sarcoma or
• 3) B-cell lymphoma, accompanied by a profound decrease in the
number of CD4 T cells.
• HIV is a worldwide pandemic
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• HIV, an enveloped virus, belongs to a group of retroviruses
called the lentiviruses.
• The virus particle, contains two copies of an RNA genome,
• These viral RNAs are transcribed into DNA in the infected
cell and integrated into the host cell chromosome.
• RNA transcripts produced from the integrated viral DNA
serve as
mRNA to direct the synthesis of the viral proteins, and later
the RNA genomes of new viral particles
• HIV enters cells by means of two viral glycoproteins present
in the viral envelope:
Gp120
Gp41,

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• During HIV infection, gp120 binds onto
CD4 molecules on surface of host cell (CD4+ T cells,
dendritic cells, macrophages) &
a co-receptor (CXCR4 on activated T cells & CCR5
(on dendritic cells, macrophages, and CD4 T cells) in
the membrane of the host cell.
• These co-receptors are chemokine receptors
• Following binding of gp120 to the receptor and co-
receptor, gp41 then causes fusion of the viral
envelope and the plasma membrane of the cell.
• the viral genome and associated enzymes then
enter the cytoplasm.

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• The associated viral enzymes are
reverse transcriptase, and
integrase,
• Reverse transcriptase transcribes the viral RNA into a
complementary DNA (cDNA) copy.
• An anti complement strand of DNA forms to give rise to double
stranded DNA.
• The double stranded cDNA can either circularise or integrate into
the host cell genome (as provirus) by the help of viral integrase.
• Virus replication is initiated by transcription of the provirus
• the HIV provirus can sometimes remains quiescent/dormant; i.e.
latent infection, especially in memory CD4 T cells and dormant
macrophages (which act as reservoirs of the infection).
• Transcription of the HIV provirus depends on host cell
transcription factors induced upon the activation of infected T
cells
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• There are four major HIV genomes, referred to as
• gag (structural proteins),
• pol (polymerase),
• env (envelope glycoproteins), and
• tat (trans-activatory of transcription).
• The tat and gag genes are very important in facilitating transcription of viral
genome and viral assembly, respectively.
• When HIV is activated and viral transcription occurs, viral inactive precursor
protein, gag-pol protein is formed.
• The gag-pol protein then cleaves to form the active proteins, such as viral
proteases, p24, reverse transcriptase, and integrase.
• Once active proteins are formed, assembly into infectious particles can take place.
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NB

Drug targets for arresting viral

replication include
• Viral reverse transcriptase (for
synthesis of the provirus) and
• viral protease (which cleaves
viral polyproteins to produce
virion proteins).
• Inhibitors of these enzymes prevent
the establishment of further
infection in uninfected cells.

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HIV induces strong cellular and humoral immune responses

CTL- cytotoxic T lymphocytes (CD8 killer T cells)

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CD4 T cells are depleted in the course of HIV infection

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Some terminologies of HIV infection
• The Window Period of HIV infection is the time lag
between when the immune system produces HIV antibodies, and
when these antibodies can be detected using an HIV antibody test.
• It can take between 2-12 weeks before the immune system
produces enough antibodies to be detected.
• Hence, if a test taken in the window period comes back negative,
a second test should be taken 12 weeks later.
• Transmission can occur during this period so safe sex should be
practised.
• Seroconversion: When antibodies have been produced and
detected, seroconversion is said to have taken place.
• Seroconversion illness may take the form of mild influenza type
symptoms or a rash.
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• Asymptomatic Phase: starts from the point of
seroconversion, the person is HIV positive. This can
only be confirmed by an HIV antibody test. During
this phase the HIV positive person does not show any
major symptoms related to HIV infection.
• AIDS: HIV positive persons are given a diagnosis of
AIDS if they develop two or more opportunistic
illnesses simultaneously, and/or have a CD4 cell
count below 200 cells/ul.

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Why is HIV not cleared by the immune system?

• High mutation rate of HIV

 Mutations that occur as HIV replicates allow variants of the virus
to escape recognition by antibody or CTLs.
 HIV latency
 Some HIV infected cells go into a resting state and stop producing
HIV, thus forming latent HIV reservoir.
 Compromised immune function, primarily through the loss
of CD4 TH cells

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 Innate immune system vs HIV

Innate responses against HIV HIV counter-attack

• Rapid and first line of defense against • The virus can infect members of
the virus the innate immune system
• Alert and activate the adaptive • Innate cells can act as depot/
immune response reservoirs and effectively
• Release pro-inflammatory signals transmit virus
• Clearance of infected cells • Inhibition of function via viral
• Internalize and process the virus to factor release and/or improper
present to T cells to initiate the immune signals
adaptive response

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 CD4 T cells vs HIV

CD4 T cells responses against HIV HIV counter-attack

• Orchestrate adaptive immune • Infects CD4 T cells
response • Causes depletion of the CD4
• Activated by innate immune T cell population and thereby
system removes the “brains” of the
• Facilitate CD8 T cell (killer) and immune response****
B cell activation • Uses surviving CD4 T cells
• Provide signals and growth as a reservoir (latent HIV)
factors for proper immune
responses

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 B cells vs HIV

B cell responses against HIV HIV counter-attack

• Directed by CD4 T cell to make • Virus mutates at a very high rate
antibodies against HIV • Loss of CD4 T cells results in:
• Antibodies neutralize the virus – Increase in numbers of
to prevent spread immature B cells
– Exhaustion
– Decreased memory

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 CD8 T cells vs HIV

CD8 T cells responses against HIV HIV counter-attack

• Killer arm of the immune system • Virus mutates and escapes
• Seek, identify and destroy • Chronic inflammation leads
infected cells to exhaustion
• Control virus in the initial months • Lack of CD4 T cells:
of infection a. Insufficient signals to
activate more killer cells
b. Defective memory
c. Impaired function

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***Why are CD4 T cells depleted during the course of HIV infection?
1. Direct viral destruction of infected cells
 HIV has the ability to ‘lock on’ to the surface of the CD4 T cells, the very cell that helps start
off the immune response.
 HIV then enters the cell, where it begins to reproduce.
 During this process it copies the unique DNA code of the host cell, so that new HIV cells are no
longer identified by the body as foreign therefore the immune system no longer responds to
them.
 HIV multiplies inside the CD4 cell. When the CD4 cell is full of HIV, it breaks open, killing the
CD4 cell, and releasing more HIV into the bloodstream.
 The virus will continue to invade and destroy CD4 cells.
2. Increase susceptibility to induction of apoptosis in infected cells
3. CTL killing of infected CD4 T cells
4. The binding of CD4 by gp120 can damage CD4 T cells even if they not
actually infected with the virus.
 Eventually the body cannot replace the CD4 cells fast enough, and the
immune system deteriorates.
 When the immune system deteriorates to the point that it is unable to
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fight off diseases, a person is diagnosed with AIDS.
Clinical Sequelae of HIV Progression
• Increased HIV load correlates with Decline in CD4 cells; both relate with
clinical presentation.
• CD4 cell count <500 cells/mm3 results in increased incidences of Kaposi’s
sarcoma and AIDS-related lymphoma (non-Hodgkin’s lymphoma).
• CD4 count <200 cell/mm3 leads to high risks of opportunistic infections
(Pneumocystis jirovani pneumonia, Toxoplasma gondii, Cryptococcus
neoformans, Candida sp, Cytomegalovirus, Cryptosporium sp, Microsporium sp).
• Cytomegalovirus, Herpes simplex and Varicella zoster may also reactivate in
patients who have been previously exposed.
• In females, clinical manifestation may include recurrent vaginitis, venereal warts.
• All these are signs and symptoms of immune breakdown; (host defence is unable
to control pathogens that are in the environment from developing into clinical
disease).

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Summary
 APCs, B cells, CD4 and CD8 T cells work together to
fight infection.
 HIV perturbs APCs function, and kills CD4 T cells.
 This allows secondary “opportunistic” infections to
occur, leading to disease/death.
 Vaccines have the potential to halt HIV infection, so
far an efficacious vaccine strategy has proven elusive.
 A vaccine approach that takes into account all aspects
of the immune response will likely have the best
chance of success.
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