What HIV Does in the Body

J2J
XIV International AIDS Conference
Barcelona, July 4, 2002
Mark Schoofs
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 AIDS is a disease of the
IMMUNE SYSTEM
• Just as hepatitis destroys the liver, HIV destroys the
immune system
• The immune system is not one localized organ, like
the liver, but a network of cells and organs
• HIV, the cause of AIDS, primarily attacks one type
of cell that is crucial to the immune system: The
CD4 T-helper cell
• The consequence is that the body cannot fight off
infections, and so it succumbs to “opportunistic
infections” such as TB, pneumonia, etc.
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 AIDS is caused by HIV,
the Human Immunodeficiency Virus

Courtesy of Anthony S. Fauci, National Institute of Allergy and Infectious Diseases

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 In many ways
HIV acts like most other viruses

And the immune system treats it

like any other virus

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 But in a few crucial ways
HIV differs from other viruses

 HIV attacks the immune system itself

and even turns the immune system counter-

attack to its own advantage

 This allows HIV to persist in the body for years
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 The immune system is a
network of organs and cells
• Mucosal barriers:
Vagina, rectum,
mouth.
• Lymphatic vessels:
the immune system’s
bloodstream
• Lymph nodes &
GALT: cleansing
centers
• Thymus, spleen, bone
marrow etc.
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Images from The National Cancer Institute, http://newscenter.cancer.gov/sciencebehind/immune/immune00.htm
Slide courtesy of Anthony S. Fauci, National Institute of Allergy and Infectious Diseases 7
 The immune system is complex
and interactive
• Immune-system cells detect invading viruses and
bacteria
• Immune system cells mobilize each other by:
– Direct cell-to-cell contact
– Excreting messenger molecules such as “cytokines”
• Immune system cells destroy invading viruses by:
– Excreting “antibodies” that snare free-floating virus
– Killing the body’s own cells that have been infected
– Excreting molecules such as “chemokines” that interfere with
viral replication

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Slide courtesy of Anthony S. Fauci, National Institute of Allergy and Infectious Diseases
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 The CD4+ T-helper Cell
• “CD4+” means that the cell displays (“expresses”)
a molecule on its surface called “CD4”. HIV
attaches to this molecule and, like a lock and key,
uses it to enter the cell.
• “Helper” means that this cell “helps” other parts of
the immune system do their job. If the immune
system is an orchestra, this cell is the conductor.
• “T” is short for “Thymus-derived” and is a type of
immune cell. There are other T-cells, such as killer
T-cells.
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 HIV replicates in CD4 cells. Amount of
virus produced determines disease course

New virus
assembly

2-3 Days
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Slide (slightly adapted) courtesy of Bruce D. Walker, Massachusetts General Hospital, Harvard Medical School, Partners AIDS Research Center
Typical Course of HIV infection

Graph courtesy of Anthony S. Fauci, National Institute of Allergy and Infectious Diseases 12
Relationship Between CD4 and
Plasma HIV viral load
• AIDS is like a train
heading toward a
crash
• Viral load indicates
the speed of the train
• CD4 count indicates
the distance to the
crash

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 CD4 Count
in Phases of HIV Infection

Incubation

Primary
Presymptomatic
CD4 cell count

AIDS

5-14 days 1-4 mo. 4-10 years 1-2 years

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Slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota
 The level of HIV in the blood
Amount of Virus in Blood
predicts disease course

Rapid Progression

Slow Progression

One year
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Slide (slightly adapted) courtesy of Bruce D. Walker, Massachusetts General Hospital, Harvard Medical School, Partners AIDS Research Center
 Immune system detects HIV
and sounds the alarm
• Macrophages and dendritic cells “eat” HIV
– “Macrophage” comes from “macro” for big and “phage” for eat. So
macrophages are “Big Eaters,” or scavenger cells
• These scavenger cells cut up the virus into fragments called
“antigens” or “epitopes”
• They “present” these viral fragments to other cells, including
CD4+ T-cells
– Each CD4+ T-cell can recognize only one epitope
– When it meets its particular epitope, the CD4 T-cell clones itself into an
army of identical cells
• These “activated” cells stimulate other immune-system cells, such
as B-cells, which make antibodies, and killer T-cells, which kill
infected cells 16
 Function of the CD4 T Cell
Macrophage, Dendritic Cell,
or other Antigen Presenting Cell
Promote B-cell Antibody
Response (also called
“Humoral” response)
Activated CD4
Cell
Promote Killer T-cells
(also called “CTL”
Resting CD4 short for “Cytotoxic
Cell T-Lymphocyte”)

Secrete ß Chemokines
Rantes
Mip 1 alpha
Mip 1 ß 17
Slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota
 HIV prefers to infect
activated CD4 T-cells

• 93-99% of HIV infects activated CD4 cells.

These cells are HIV’s favorite “food”
– HIV occasionally infects unactivated or
“resting” CD4 cells, where for years it can lie
dormant, hiding from the immune system

• By activating CD4 cells to mobilize a

counterattack, the immune system is
“feeding” HIV!
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 Function of the CD4 T Cell
Macrophage, Dendritic Cell,
or other Antigen Presenting Cell
Promote B-cell Antibody
Response (also called
“Humoral” response)
Activated CD4
Cell
Promote Killer T-cells
(also called “CTL”
Resting CD4 short for “Cytotoxic
Cell T-Lymphocyte”)

Secrete ß Chemokines
Rantes
Mip 1 alpha
Mip 1 ß 19
Slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota
 Antibodies try to snare HIV

New virus
assembly
B cell

Slide (slightly adapted) courtesy of Bruce D. Walker, Massachusetts General Hospital, 20

Harvard Medical School, Partners AIDS Research Center
 How antibodies work
• Antibodies work by
binding to particular
fragments of HIV as the
virus floats in the blood
or lymph.
• These fragments are
called “epitopes.”
• When the antibody
binds to the epitope, it
“neutralizes” the virus,
rendering it harmless.
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Graphic (slightly adapted) courtesy of Bruce D. Walker, Massachusetts General Hospital, Harvard Medical School, Partners AIDS Research Center
 HIV eludes antibodies
• But HIV is sheathed in an
“envelope”
– The envelope is the most
mutable part of HIV, so HIV
keeps changing its coat,
making it impossible for
antibodies to bind.
• HIV uses part of the
envelope to enter cells
– But these critical parts are
cloaked with carbohydrates
molecules. Antibodies rarely
bind effectively to
carbohydrates.

Image from The National Cancer Institute, http://newscenter.cancer.gov/sciencebehind/immune/immune00.htm 22

 Killer T-cells
are “big guns” in viral infections

• Antibodies snare free-floating virus

• But viruses infiltrate cells
– They turn the cells into factories that churn out
thousands of copies of themselves
– Inside the cells, they are protected from antibodies
– HIV also mutates to escape the antibodies
• Killer T-cells kill cells that HIV has infected

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HIV replicates mainly in lymph tissue,
the immune-system stronghold

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Images from The National Cancer Institute, http://newscenter.cancer.gov/sciencebehind/immune/immune00.htm
Site of HIV Production and Storage

Lymph tissue with HIV stained Close up of several cells in

to look bright. “Stars” are cells lymph tissue producing HIV
producing HIV.
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Photos and slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota
 HIV in the lymph nodes
• The lymph nodes normally trap viruses in the lymphoid “germinal
centers” and cleanse the viruses from the body.
• The lymph nodes trap HIV, but doing so activates CD4 T-cells.
Therefore, lymph nodes provide “food” for HIV: activated CD4+ T-
cells.
• HIV prefers to be in the very place where the immune system kills
most other viruses. HIV sets up camp in the immune system’s
stronghold.
• But: The fight between HIV and the immune system is balanced at a
standoff for many years

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 27
Slide courtesy of Anthony S. Fauci, National Institute of Allergy and Infectious Diseases
 HIV destroys the lymph nodes
• HIV causes persistent lymph-node swelling, or
“lymphadenopathy,” one of the signs of HIV
infection.
• Chronic, long-lasting activation of the immune
system, combined with HIV’s disruption of the
normal immune regulation, causes physical
destruction of the lymph nodes.
• The lymph nodes can no longer trap and destroy
HIV. The “delicate balance” tips in favor of HIV.
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 Lymph tissue in HIV-negative
and HIV-positive people

HIV-negative HIV-positive
person for 5 years, no
ARV treatment
Upper left-hand corner: round All “geographical”
germinal center surrounded features destroyed—no
by healthy mantle discernible germinal centers
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Photos and information courtesy of Timothy Schacker, University of Minnesota
The consequences of HIV infection
• As HIV slowly wins the battle, the immune system can
no longer repel some infections.
– These are called “opportunistic infections” (OIs for short)
because they take the “opportunity” given to them by the
weakened immune system.
• These other infections are what kills people. HIV itself
does not (though it can cause dementia.)

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 Antiretroviral drugs attack
HIV itself
• They stop HIV from replicating, but they do not
eradicate HIV from the body
• They allow the immune system to recover
– Not full immune reconstitution. Lymphoid tissue often
retains signs of damage; CD4 cells often don’t rise to pre-
HIV levels.
– But usually enough immune recovery to fight off most
infections.
• Therefore, ARVs take the place of drugs to prevent or
treat most OIs
• But antiretroviral drugs are expensive
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 Antiretroviral drugs (ARVs) block
HIV’s assault on the CD4 T-cell
Macrophage, Dendritic Cell,
or other Antigen Presenting Cell
Promote B-cell Antibody
Response (also called
“Humoral” response)
Activated CD4
Cell
Promote Killer T-cells
(also called “CTL”
Resting CD4 short for “Cytotoxic
Cell T-Lymphocyte”)
ARVs
Secrete ß Chemokines
Rantes
Mip 1alpha
Slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota. ARV graphic (slightly adapted) courtesy
Mip 1 ß 32
of Bruce D. Walker, Massachusetts General Hospital, Harvard Medical School, Partners AIDS Research Center
 Lymph nodes in HIV-negative, HIV-
positive, and ARV-treated patients

HIV-negative HIV-positive The same HIV-positive

person for 5 years, no patient after 6 months
ARV treatment on ARV treatment
Upper left-hand corner: All “geographical” Germinal centers discernible
Round “germinal center” features destroyed—no again but lack healthy
surrounded by healthy mantle discernible germinal centers surrounding mantle
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Photos and information courtesy of Timothy Schacker, University of Minnesota
 Without ARVs, many “OIs” can
be cured or prevented cheaply
• Tuberculosis • Can be prevented short-term
with INH. Cured with
combination antibiotics.
• Can be prevented with
• Pneumocystis Carinii Cotrimoxazole (Bactrim) and
Peumonia cured with that and other
antibiotics.

• Thrush (candidiasis) • Can be cured with fluconazole.

• Can be cured and prevented

• Cyrptococcal from recurring with
meningitis fluconzazole.

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 Treatment & prevention for OIs
often is lacking despite low cost
• Cotrimoxazole should be available in every
country.
• Generic fluconazole has been up to 95%
cheaper than Pfizer’s patented version
• TB drug supply is often a problem in
developing countries but should not be
tolerated
• These basic drugs can extend life: How is
your country doing at providing them?
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 Acknowledgements
• Anthony S. Fauci & Greg Folkers, National Institute
of Allergy and Infectious Diseases
• Bruce D. Walker & Marylyn Addo, Massachusetts
General Hospital, Harvard Medical School, Partners
AIDS Research Center
• Timothy Schacker, University of Minnesota
• Laurie Garrett, Newsday, & Omololu Falobi,
Journalists Against AIDS Nigeria
• Bob Meyers & Nena Uche, National Press
Foundation
• The Wall Street Journal & The Village Voice
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