HIV

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HIV AIDS in the United States

• AIDS deaths in the U.S. decreased by 42 from
  1996 - 97
• gt1,000,000 Men, Women Children were living
  with HIV in 2004
• gt45,000 new infections in 2004
• Women accounted for gt30 of new HIV diagnoses in
  adults

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U.S. HIV AIDS by Race/Ethnicity since 1999

• Among new AIDS cases in men, 61 were in African
  Americans and Hispanics
• Among new AIDS cases in women, 80 were in
  African Americans and Hispanics
• AIDS is now the 1 killer of African American
  women age 25 - 34
• HIV incidence among African Americans is now 8
  times higher than among Caucasians

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U.S. versus GLOBAL HIV NUMBERS

• HIV infection is more common than previously
  thought gt40 million now HIV infected
• 5 million infected in 2004 _at_ a rate of
  14,000/day
• 2000 in children lt15 y.o.
• 12,000 in persons 15 - 49 y.o.
• (50 women 50 15 - 24 y.o.)
• ? 1 of sexually active adults are infected
• ? 90 of the infected don't know it!
• ? gt3 million died from AIDS in 2004
• - 60 more than in 1996
• gt33 were Adult women
• 20 were under 15 years old

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In Sub-Saharan Africa
? 8 of 15-49 years old are infected ? In
Botswana, Zimbabwe, Nigeria, Swaziland 25 -
30 of adults are infected ? In large towns of
Zimbabwe 70 of pregnant women are infected
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Causes of deaths, globally and in Africa
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19
18
16
14
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Global
10
Percent of deaths
Africa
8
6
4.2
4
2.8
2.3
2.2
2
0.3
0
HIV/AIDS
Tuberculosis
Lung cancer
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Projected changes in life expectancy in selected
African countries with high HIV prevalence,
19952000
65 60 55 50 45 40 35
Average life expectancy at birth, in years
Botswana
Zimbabwe
Zambia
Uganda
Malawi
1955
1960
1965
1970
1975
1980
1985
1990
1995
2000
Source United Nations Population Division, 1996
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HIV prevalence rate among teenagers in Kisumu,
Kenya, by age
35
33.3
29.4
30
25
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HIV prevalence ()
20
17.9
boys
girls
15
8.6
8.3
10
3.6
5
2.2
0
0
0
15
16
17
18
19
Age in years
Source National AIDS Programme, Kenya, and
Population Council, 1999
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Much of what we took for granted has been proven
wrong...
despite the most concerted effort of medical
research in modern history. e.g. - Exclusive
CD4 cell tropism - Idea of viral dormancy etc.
- Combination therapy
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CO-OPTION AND DESTRUCTION OF THE IMMUNE SYSTEM BY
HIV
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OVERVIEW OF THE HIV LIFECYCLE
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OVERVIEW OF THE HIV LIFECYCLE
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CLINICAL COURSE OF HIV INFECTION
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Dynamics of CD4 cell Numbers during HIV Disease
Surprising finding of very high rates of HIV
replication CD4 cell turnover in HIV
patients Current estimates of 100 billion new
HIV particles / day 1 - 2 billion CD4 cells are
killed and regenerated / day
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ALTERNATIVE RECEPTORS FOR HIV (CD4-INDEPENDENT)
CD4- cells can be infected by HIV e.g.
Bowel/Renal epithelia
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(1) GalC - Galactosyl ceramide

• A glycolipid
• may cluster with other glycolipids
• ? Form lipid rafts CD4
• HIV infects cultured neuronal cell lines
• anti-GalC Abs block in both CD4- cell lines ?
  some accumulation on surface

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(2) Pseudotype Viruses in HIV Infection

• Formation of chimeric viruses where one viral
  genome can be encapsulated within a different
  viral envelope
• - created in vitro by co-infection with two
  viruses
• HIV pseudotypes observed include
• HIV-1 HIV-2
• HIV-1 HTLV-I
• HIV murine retroviruses
• HIV herpes viruses e.g. HSV

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DIRECT TOXIC EFFECTS OF HIV PROTEINS
Primarily via changes in the cell membrane (a)
Auto Fusion Evidence for a loss in osmotic
balance ? decrease in intracellular ionic
strength ? results in cell ballooning and lysis
(b) Cultured brain cells exposed to gp120 show an
influx of Ca2 ? overactivation of Ca2 Kinases
etc. ? Reversed by nimodipine - Ca channel
antagonist
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HIV-induced Apoptosis via Fas Receptor
The FasL/Fas (CD95) ligand/receptor complex
helps maintain lymphocyte homeostasis
via cell depletion
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Fas/FasL Mechanism of Action
CAD (caspase-activatable DNase)
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Observation uninfected T-cells from HIV Patients

• Have a higher degree of activation
• Have ? Fas expression on their surface
• Are more sensitive to FasL induction of
  apoptosis
• HIV infection of macrophages/monocytes
  increases the production of FasL
• ? Uninfected T-cells undergo apoptosis when
  cocultured (Contact necessary)

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• Human APCs, macrophages can produce FasL and are
  upregulated when HIV infected
• This elevated level of FasL expression can induce
  apoptosis in uninfected T-cells (by contact)
• IN THE CENTRAL NERVOUS SYSTEM
• soluble FasL also detected in cerebrospinal fluid
  (CSF) samples from HIV-infected patients
• ? may contribute to brain injury with
  progression to AIDS
• specifically targets astrocytes and glial cells