What HIV Does in the Body

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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 theIMMUNE 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
4
In many waysHIV acts like most other viruses

• And the immune system treats it
• like any other virus

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But in a few crucial waysHIV 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
  
• and finally destroy the immune system

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The immune system is a network of organs and
cells

• Mucosal barriers Vagina, rectum, mouth.
• Lymphatic vessels
• the immune systems 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 bodys 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
10
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
Slide (slightly adapted) courtesy of Bruce D.
Walker, Massachusetts General Hospital, Harvard
Medical School, Partners AIDS Research Center
12
Typical Course of HIV infection
Graph courtesy of Anthony S. Fauci, National
Institute of Allergy and Infectious Diseases
13
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
Slide (slightly adapted) courtesy of Timothy
Schacker, University of Minnesota
15
The level of HIV in the bloodpredicts disease
course
Rapid Progression
Amount of Virus in Blood
Slow Progression
Slide (slightly adapted) courtesy of Bruce D.
Walker, Massachusetts General Hospital, Harvard
Medical School, Partners AIDS Research Center
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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

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

• 93-99 of HIV infects activated CD4 cells. These
  cells are HIVs 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)
Resting CD4 Cell
Secrete ß Chemokines
Rantes Mip 1 alpha Mip 1 ß
Slide (slightly adapted) courtesy of Timothy
Schacker, University of Minnesota
20
Antibodies try to snare HIV
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.

Graphic (slightly adapted) courtesy of Bruce D.
Walker, Massachusetts General Hospital, Harvard
Medical School, Partners AIDS Research Center
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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
Images from The National Cancer Institute,
http//newscenter.cancer.gov/sciencebehind/immune/
immune00.htm
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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
Photos and slide (slightly adapted) courtesy of
Timothy Schacker, University of Minnesota
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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 systems 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
28
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 HIVs 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-positive for 5 years, no ARV treatment All
geographical features destroyedno discernible
germinal centers
HIV-negative person Upper left-hand corner
round germinal center surrounded by healthy
mantle
Photos and information courtesy of Timothy
Schacker, University of Minnesota
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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
  dont 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 HIVs 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)
Resting CD4 Cell
Secrete ß Chemokines
Rantes Mip 1alpha Mip 1 ß
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
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Lymph nodes in HIV-negative, HIV-positive, 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 destroyedno discernible
germinal centers
The same HIV-positive patient after 6 months on
ARV treatment Germinal centers discernible again
but lack healthy surrounding mantle
Photos and information courtesy of Timothy
Schacker, University of Minnesota
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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 Pfizers 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