HIV and AIDS

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HIV and AIDS
Acquired Immunodeficiency Syndrome A disease
caused by an infectious agent a retrovirus
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HIV and AIDS
History of AIDS 1979 onwards
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HIV and AIDSHistory of an infectious agent
In Los Angeles 1967-1978 only two cases of
Pneumocystis carinii pneumonia
A rare opportunistic infection seen in
immunocompromized patients

• 1979 - 5 cases of Pneumocystis carinii pneumonia

All Homosexual
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HIV and AIDSHistory of an infectious agent
Dot-like intracystic bodies of Pneumocystis
carinii in lung Cytologic preparation from a
bronchoalveolar lavage Giemsa stain and silver
stain
Renamed Pneumocystis jiroveci A fungus
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HIV and AIDSHistory of an infectious agent
Pneumocystis pneumonia
107 cases of Pneumocystis pneumonia reported in
the United States before the AIDS epidemic AIDS
epidemic resulted in 166,368 cases up to 1999
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HIV and AIDS
With dissemination to extrapulmonary sites,
Pneumocystis jiroveci tends to produce foci with
prominent calcification, as seen in the kidney
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HIV and AIDSHistory of an infectious agent
Kaposis sarcoma was rare, usually indolent and
found in the elderly It is associated with
immunocompromization

• 1981 - 26 cases of Kaposis sarcoma
• Young
• Male
• Cluster
• San Francisco and New York

• All Homosexuals

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HIV and AIDSKaposis Sarcoma
Before 1981 40 - 120 cases per year in United
States
1981-1999 46,684 definite cases in United States
Intraoral Kaposis sarcoma lesion with an
overlying candidiasis infection
KS affects about 20 of people with AIDS who
aren't taking anti-HIV drugs. The rate of KS has
dropped by over 80 since the introduction of
HAART
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HIV and AIDS
Two rare diseases in the gay community linked
to IMMUNOSUPPRESSION OPPORTUNISTIC INFECTIONS
Also Lymphadenopathy (diffuse, undifferentiated
non-Hodgkins lymphoma) 1977- 1980 No cases in
the young male (20 - 39 years old) population of
the San Francisco area March 1981 - January
1982 four cases within 10 months
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HIV and AIDS

• Kaposi's Sarcoma and Opportunistic Infections
  (KSOI )
• Gay-Related Immune Deficiency (GRID)
• ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

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HIV and AIDS

• Little in common except
• Young
• White
• Male
• Large towns
• Homosexual community

But not all gay men got the disease
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HIV and AIDS
Distinguishing characteristics

• Clusters of infected men
• Apparent concentration within sexually
  interactive groups
• High numbers of sex partners

Suggests an infectious agent
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HIV and AIDS
More evidence for an infectious agent came in
1982 Different ways of getting a similar syndrome

• Blood transfusions

• Intravenous drug use

• Hemophilia (clotting factor)

Female sex partners of AIDS-positive IV drug
users and hemophiliacs
Not just in the Gay community
Haitian origin
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HIV and AIDS
1983 The 4H Club

• Homosexuality among males
• Hemophilia
• Heroin use (drug use that may involve shared
  needles)
• Haitian origin

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HIV and AIDS
Obvious agent A virusthat is now in the blood
supply Primary route of transmission Sex
AIDS is a sexually-transmitted viral disease
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A disease of immunocompromization WHAT IS GOING
ON IN THE IMMUNE SYSTEM? The cellular picture
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HIV and AIDSThe Cellular Picture
Loss of one cell type throughout the course of
the disease CD4 T4 helper cells A fall in the
CD4 cells always precedes disease
In advanced disease the loss of another cell
type CD8 cytotoxic killer cells
Suggests an infectious agent A virus But
initially difficult to grow Rapidly kills cells
on which it grows
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AIDS Definition

• AIDS is currently defined as the presence of one
  of 25 conditions indicative of severe
  immunosuppression

• OR
• HIV infection in an individual with a CD4 cell
  count of lt200 cells per cubic mm of blood

• AIDS is therefore the end point of an infection
  that is continuous, progressive and pathogenic
• With the prevalence of HIV in the developing
  world, HIV and its complications will be with us
  for generations

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STATISTICS
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• Approximately 33,000,000 people in the world are
  HIV-infected
• Approximately 14,000 new HIV infections occur
  daily around the world
• Over 90 of these are in developing countries
• 1000 are in children less than 15 years of age
• Of adult infections, 48 are in women and 15 in
  individuals 15 to 25 years

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AIDS Statistics

• As of December 2006, 1,106,400 Americans have
  been reported with AIDS
• At least half of them have died
• 9,101 children under 15

• Over ONE MILLION persons in the United States are
  living with HIV infection
• 828,000 men
• 278,000 women
• Over 50,000 new infections per year (53 in gay
  men)

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HIV and AIDS
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HIV and AIDS
Prevalence
AIDS disease
Deaths
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HIV and AIDS
Black
White
Hispanic
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AIDS Statistics

• Sub-Saharan Africa
• About 1 million new cases of AIDS per year
• At least 20 million people with HIV infection
• AIDS is responsible for a decrease in life
  expectancy and increase in child mortality. Child
  mortality rates in East Africa will double by
  2010 and adult life expectancy has declined in
  that region

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AIDS Statistics
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AIDS Statistics
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AIDS Statistics

• Several countries in sub-Saharan Africa report
  infection rates of over 25, especially urban
  areas
• Zimbabwe 33.7 of adult population infected
• 90 of truck drivers in Zimbabwe are infected
• In Zambia, 1 in 5 urban girls is HIV-positive by
  the age of 20

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AIDS Statistics
End of 2008 20 million people in sub-Saharan
Africa had an HIV infection 4 million receiving
treatment (up from 3 million in 2007)
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AIDS THE COURSE OF THE DISEASE
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HIV and AIDS
The cellular and immunological picture - The
course of the disease
virus
antibody
CD4 cells
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HIV and AIDS
The cellular and immunological picture - The
course of the disease
CD8 cells
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HIV and AIDS
The cellular and immunological picture The course
of the disease 1. Acute Infection

• High virus titer
• Mild symptoms
• Fall in CD4 cells but recovers
• Rise in CD8 cells but recovers
• A high virus titer (up to 10 million viruses per
  ml blood)
• Gut CD4 cells depleted
• Acute immunological activation state is set up
• Macrophages and CD4 cells infected

Macrophages bring HIV into the body if sexually
transmitted
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HIV and AIDS
2. A strong immune response

• Virus almost disappears from circulation
• Good cytoxic T cell response
• Soluble antibodies appear later against both
  surface and internal proteins
• Most virus at this stage comes from recently
  activated (dividing) and infected CD4 cells
• CD4 cell production compensates for loss due to
  lysis of cells by virus production and
  destruction of infected cells by CTLs

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HIV and AIDS
3. A latent state

• Latency of virus and of symptoms
• Virus persists in extra-vascular tissues
• Lymph node dendritic cells
• Resting CD4 memory cells (last a very long
  time - a very stable population of cells) carry
  provirus
• There is still a state of immune activation

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HIV and AIDS

• 10 billion HIV particles per day
• Virus half life 5.7 hours
• 100-10 million virions per ml blood (set point)
• Small minority of T4 cells are infected
• Virus found in lymph nodes

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HIV and AIDS
4. The beginning of disease

• Massive loss of CD4 cells
• CD4 cells are the targets of the virus
• Cells that proliferate to respond to the virus
  are killed by it
• Dendritic cells present antigen and virus to
  CD4 cells
• Epitope variation allows more and more HIV to
  escape from immune response just as response
  wanes
• Apoptosis of CD4 cells
• HIV patients with high T4 cell counts do not
  develop AIDS

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HIV and AIDS
5. Advanced disease - AIDS

• CD8 cells destroy more CD4 cells
• CD4 cell loss means virus and infected cells no
  longer controlled
• As CD4 cells fall below 200 per cu mmvirus
  titer rises rapidly and remaining immune response
  collapses
• CD8 cell number collapses
• Opportunistic infections
• Death in 2 years without intervention

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HIV and AIDS
Good correlation between number of HIV
particles measured by PCR and progression to
disease
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HIV and AIDS
Viral load predicts survival time
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HIV and AIDS
CD4 cell count is not a good predictor of
progression to disease
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Cofactors
HIV and AIDS
Not all cases of Kaposis are associated with
HIV Not all HIV infected persons suffer from
Kaposis 20 of homosexual HIV males get
Kaposis Few IV drug users or hemophiliacs get
Kaposis
Kaposis sarcoma associated herpes virus Human
herpes virus-8
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HIV and AIDS
Three Views of AIDS
Gallo Infection by HIV is sufficient to cause
AIDS
Montagnier HIV may be harmless in the absence of
other co-factors
Duesberg / Mullis HIV is too silent to be the
etiologic agent of AIDS. It is a much maligned
by-stander
So far it seems that gt50 of HIV-infected persons
have progressed to AIDS There is NO evidence
there is any other infectious agent involved than
HIV
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Human Immunodeficiency Virus
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HIV and AIDSThe Virus

• The virus only grows on T4 cells that are
  proliferating in response to an immune stimulus
  -- Therefore difficult to grow in culture
• Reverse transcriptase in activated T4 cells in
  blood of patients with AIDS
• Robert Gallo HTLV-3
• Luc Montagnier and Françoise
  Barré-Sinoussi LAV

Human Immunodeficiency Virus (HIV)
Human immunodeficiency viral particles are seen
at medium magnification in this electron
micrograph (CDC)
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HIV - The Virus
Retrovirus
Membrane host derived
Three genes GAG POL ENV Three polyproteins
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HIV - The Virus
Retrovirus
ENV gene
vaccine problem
vaccine problem
Trimer
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HIV - The Virus
Retrovirus
Group-Specific Antigens
GAG gene
Polyprotein
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HIV - The Virus
Retrovirus
Enzymes

• Polymerase (reverse transcriptase RNA
  dependent DNA polymerase, RNase H)
• Integrase
• Protease (cuts polyproteins)

• POL gene

Polyprotein
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The Genome of HIV
Three structural genes LTRs Extra open reading
frames are clue to latency These ORFs code for
small proteins - antibodies in AIDS patients
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HIV - The Virus
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HIV - The Virus
Life History

• A retrovirus
• Latency
• Specific destruction of CD4 cells
• How does the virus enter the cell?

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HIV - Life History

• Fusion at ambient pH
• No need for entry into lysosomes
• Syncytia

Profound significance for AIDS progression
Spread from cell to cell Profound significance
for therapyHumoral antibody will not stop
spread need cell-mediated response
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HIV - Life History
HIV is a retrovirus It carries with it

• Reverse transcriptase
• Integrase
• Protease
• tRNA primer

HIV genes
GAG POL ENV
HIV has no oncogene but could still be oncogenic
vaccine problem
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HIV - Life History
Entry into the cell
Human HeLa Cell transfected with CD4 antigen
Human HeLa Cell
NOT INFECTED
INFECTED
T4 (CD4) cells are major target because they
express CD4 antigen and it is the HIV receptor
But NOT the whole answer since this does not
happen if CD4 is transfected into a MOUSE cell
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HIV - Life History
Why do CD4-transfected human cells become
infected but CD4-transfected mouse cells do not?
Human cells must possess a co-factor for
infection that mouse cells do not
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HIV - Life History
HIV
chemokine
Mutant CCR5
CD4
CCR5
CD4
CCR5
CD4
macrophage
Chemokine receptors are necessary co-receptors
along with CD4 antigen GP120 can only interact
with a chemokine receptor after binding CD4
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HIV and AIDSSome people do not get AIDS
Long term survivors Exposed uninfected persons
The chemokine receptor story
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HIV and AIDS

• Co-receptors and HIV infection
• CCR5 is a chemokine receptor
• Cells with a homozygous deletion mutation in
  CCR5 molecules are not infected by HIV
• 1 in 100 Caucasians
• No Africans
• Persons with heterozygous mutant CCR5 molecules
  progress to AIDS more slowly

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HIV and AIDS

• Co-receptors
• 25 of long term survivors are CCR5 or CCR2
  mutants (deletions)

• The same CCR5 mutation (called delta 32) is
  thought to be the mutation that rendered some
  people immune to the plague in the middle ages

• Many other chemokine receptors

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Long term non-progressersSuper suppressors
HIV and AIDS

• People who have been infected with HIV for more
  than seven years that have stable CD4 cell
  counts above 600 per cu mm with no symptoms and
  no chemotherapy
• Many have produced a very good immune response
  to the virus

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HIV and AIDS

• Nairobi prostitutes
• Client infection rate more than 25
• Rare HLA antigens
• Associations between resistance to infection and
  their class I and class II MHC (HLA) haplotypes

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HIV - Life History
Latency Cellular The problem of memory T4
cells
Only activated T4 cells can replicate virus Most
infected T4 cells are rapidly lyzed but are
replaced Some T4 cells revert to resting state as
memory cells which are long-lived Memory T4 cells
cannot replicate the virus unless they become
activated
Clinical Latency
HIV infection is not manifested as disease for
years During apparent clinical latency, virus is
being replicated and cleared
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A STATE OF IMMUNE ACTIVATION
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1. HIV attacks the very cells that should defend
against it
Activated
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1. HIV attacks the very cells that should defend
against it
Activated

• T cells activated to respond to HIV are infected
  and produce HIV
• Thereby
• Producing more substrate for HIV proliferation
• Blunting the immune response to HIV

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2. HIV sets up a state of general immune
activation for the course of the disease

• Seen in human with HIV infection
• Seen in Rhesus monkeys where SIV is pathogenic
• Only temporary in Sooty Mangabeys where SIV is
  non-pathogenic

Results in activated general CD4 cells --- are
the substrate for viral replication
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HOW DOES THIS HAPPEN?
HIV destroys CD4 cells in the intestinal wall as
they become infected These cells are never
regained Includes T17 cells that fight off
bacteria and fungi

• Barrier epithelial cells also damaged they are
  infected by HIV via a galactocerebroside receptor

• Enteropathy
• Inflammation
• Difficulty in absorbing nutrients
• Diarrhea
• Lipopolysaccharide translocated into the
  bloodstream

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Dynamics of CD4 T cells in an HIV infection
Cell deathapoptosis etc
Uninfected activated T cell
Cell deathimmunedestruction
Adapted from Saag and Kilby Nat Med 5 609, 1999
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Long term latent HIV
T4 resting memory cell
It may be impossible to cure the patient of
HIV Even if combination therapy stops HIV
replication
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Inexorable decline of CD4 T4 cells
Why do all of the T4 cells disappear?
At early stages of infection only 1 in 10,000
cells is infectedLate 1 in 40
Of great importance to therapeutic strategy
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Inexorable decline of CD4 T4 cells
Possible means of killing CD4 cells

• Lysis of infected cells as virus proliferates
  (HIV-infected cells)
• Cell mediated killing (HIV-infected cells)
• Syncytia formation (Could sweep up uninfected
  cells but rare)
• Gp120 binds to CD4 complement-mediated lysis
  (Uninfected cells)
• HIV-induced apoptosis
• Infected cells
• Uninfected cells

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Why do HIV-specific T4 cells disappear?
Antigen presenting cell
HIV-specific activated T cell
HIV-specific TCR
MHC
PD1 ligand expressed
PD1 expressed
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Antigen presenting cell
HIV-specific activated T cell
MHC
PD1 ligand and PD1 bind
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Antigen presenting cell
HIV-specific activated T cell
MHC
PD1 induces apoptosis
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Why do all T4 cells disappear?
Induction of apoptosis
T cell
Macrophage
chemokine receptor
?
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Induction of apoptosis
T cell
CXCR4
Macrophage
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Macrophages may be infected by two routes
HIV gp120 binds to macrophage CD4 antigen
HIV gp120
Virus is opsonized by anti gp120 antibodies which
bind to macrophage Fc receptors - an enhancing
antibody
CD4
Fc receptor
Anti-gp120
vaccine problem
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Macrophages - The Trojan Horse
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POPULATION POLYMORPHISM A Challenge for
Vaccinology
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Population Polymorphism
HIV is a retrovirus
Retroviruses use host cell RNA polymerase II to
replicate their genome
Pol II has a high error rate 12,000-10,000
HIV genome 9749 nucleotides Therefore EVERY new
virus has at least one mutation! Every possible
single mutation arises daily 1 of all possible
double mutations arise daily
The HIV that infects a patient is very different
from that seen by the time AIDS appears
vaccine problem
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Population Polymorphism

• Initial infecting virus is macrophage-tropic
  (has CCR5 as co-receptor)
• These are non-syncytium-inducing strains
• (Note most vaccines have been made against
  syncytium-inducing T4 cell tropic strains)
• As virus mutates, it changes subtypes of cells
  that it infects as the ability to bind different
  co-receptors changes

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Population Polymorphism

• Early in infection
• Macrophage-tropic
• Non-syncytium-inducing
• Slowly replicating

• Late in infection
• T4 cell tropic
• Syncytium-inducing
• High titer virus

vaccine problem
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Population Polymorphism

• The most variable protein is gp120
• Amino acid sequence within a single patient
  varies by 1-6
• Up to 30 in population

vaccine problem

• Glycosylation masks conserved sites

vaccine problem
Co-infection may result in recombination
vaccine problem
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Population Polymorphism

• Variation in reverse transcriptase leads to
  resistance to nucleoside analogs

drug problem

• Variation in protease leads to resistance to
  protease inhibitors

drug problem
Polymorphism due to high mutation rate as a
result of lack of proof-reading in reverse
transcriptase and RNA pol II Sub-populations
arise with altered cell tropism
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Other cells infected by HIVCD4-

• Epithelial cells of bowel and vagina
• Endothelial cells of brain
• Brains cells Astroglia, oligodendroglia
• Galactocerebroside receptor

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Anti-HIV Strategies
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Anti-HIV Strategies
Highly Active Anti- Retroviral Therapy HAART Two
nucleoside analog RT inhibitors and 1 protease
inhibitor Or Two nucleoside analog RT inhibitors
and 1 non nucleoside
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Does HIV Cause AIDS?
Single common factor between

• Gay San Franciscans
• New York I.V. drug users
• African heterosexuals
• Hemophiliacs
• Spouses of hemophiliacs and drug users
• Children of hemophiliacs and drug users

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Does HIV Cause AIDS?
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Remember!

• Education led to leveling off of rate of
  increase in AIDS
• HAART has greatly slowed death rate

• The fact that fewer people are dying per year
  from the infection means that the number of
  HIV-infected people in the population is rising!
• Unless education continues to be successful and
  unless we can cure infected people of virus, the
  problem of virus spread is, and will continue to
  be, with us