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

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

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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

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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 predicts disease course
Amount of Virus in Blood

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” short for “Cytotoxic T-Lymphocyte”) Secrete ß Chemokines Rantes Mip 1 alpha Mip 1 ß 17
Slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota

Resting CD4 Cell

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” short for “Cytotoxic T-Lymphocyte”) Secrete ß Chemokines Rantes Mip 1 alpha Mip 1 ß 19
Slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota

Resting CD4 Cell

Antibodies try to snare HIV

New virus assembly B cell

Slide (slightly adapted) courtesy of Bruce D. Walker, Massachusetts General Hospital, Harvard Medical School, Partners AIDS Research Center

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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

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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 to look bright. “Stars” are cells producing HIV.

Close up of several cells in lymph tissue 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+ Tcells. • 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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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 person
Upper left-hand corner: round germinal center surrounded by healthy mantle
Photos and information courtesy of Timothy Schacker, University of Minnesota

HIV-positive for 5 years, no ARV treatment
All “geographical” features destroyed—no discernible germinal centers
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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 preHIV 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” short for “Cytotoxic T-Lymphocyte”) Secrete ß Chemokines Rantes Mip 1alpha Mip 1 ß 32

Resting CD4 Cell

ARVs

Slide (slightly adapted) courtesy of Timothy Schacker, University of Minnesota. ARV graphic (slightly adapted) courtesy of Bruce D. Walker, Massachusetts General Hospital, Harvard Medical School, Partners AIDS Research Center

Lymph nodes in HIV-negative, HIVpositive, and ARV-treated patients

HIV-negative person
Upper left-hand corner: Round “germinal center” surrounded by healthy mantle

HIV-positive for 5 years, no ARV treatment
All “geographical” features destroyed—no discernible germinal centers

The same HIV-positive patient after 6 months on ARV treatment
Germinal centers discernible again but lack healthy 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 • Pneumocystis Carinii Peumonia • Thrush (candidiasis) • Cyrptococcal meningitis
• • Can be prevented short-term with INH. Cured with combination antibiotics. Can be prevented with Cotrimoxazole (Bactrim) and cured with that and other antibiotics. Can be cured with fluconazole. Can be cured and prevented from recurring with 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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