HIV & AIDS in the United States
• AIDS deaths in the U.S. decreased by 42% from 1996 - 97
• >1,000,000 Men, Women & Children were living with HIV in 2004
• >45,000 new infections in 2004
• Women accounted for >30% of new HIV diagnoses in adults
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
HIV infection is more common than previously thought >40 million now HIV infected
5 million infected in 2004 @ a rate of ~14,000/day
~ 2000 in children <15 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!
>3 million died from AIDS in 2004 - 60% more than in 1996
>33% were Adult women~20% were under 15 years old
U.S. versus GLOBAL HIV NUMBERS
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
In Sub-Saharan Africa:
Causes of deaths, globally and in Africa
4.2
2.82.3
19
2.2
0.30
2
4
6
8
10
12
14
16
18
20
HIV/AIDS Tuberculosis Lung cancer
Per
cen
t o
f d
eath
s
Global
Africa
Projected changes in life expectancy in selected African countries with high HIV prevalence, 1995–2000
Source: United Nations Population Division, 1996
1955 1960 1965 1970 1975 1980 1985 1990 1995 2000
Average life expectancy at birth, in years65
60
55
50
45
40
35
ZimbabweZimbabwe
ZambiaZambiaUgandaUganda
BotswanaBotswana
MalawiMalawi
HIV prevalence rate among teenagers HIV prevalence rate among teenagers in Kisumu, Kenya, by agein Kisumu, Kenya, by age
0 0
3.62.2
8.68.3
17.9
29.4
22
33.3
0
5
10
15
20
25
30
35
15 16 17 18 19Age in years
HIV
pre
vale
nc
e (%
)
boys
girls
Source: National AIDS Programme, Kenya, and Population Council, 1999
despite the most concerted effort of medical research in modern history.
e.g. - Exclusive CD4 cell tropism- Idea of viral dormancy etc. - Combination therapy
Much of what we took for granted has been proven wrong...
CO-OPTION AND DESTRUCTION OF THE IMMUNE SYSTEM BY HIV
OVERVIEW OF THE HIV LIFECYCLE
OVERVIEW OF THE HIV LIFECYCLE
CLINICAL COURSE OF HIV INFECTION
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
Dynamics of CD4 cell Numbers during HIV Disease
CD4- cells can be infected by HIV
e.g.: Bowel/Renal epithelia
ALTERNATIVE RECEPTORS FOR HIV (CD4-INDEPENDENT)
A glycolipidmay 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
(1) GalC - Galactosyl ceramide
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-2HIV-1 + HTLV-IHIV + murine retrovirusesHIV + herpes viruses e.g. HSV
(2) Pseudotype Viruses in HIV Infection
HIV
HSV
CELL
pseudotypes
Primarily via changes in the cell membrane
(a) Auto FusionEvidence for a loss in osmotic balance decrease in intracellular ionic strength results in cell ballooning and lysis
DIRECT TOXIC EFFECTS OF HIV PROTEINS
(b) Cultured brain cells exposed to gp120 show an influx of Ca2+
overactivation of Ca2+ Kinases etc.
Reversed by nimodipine - Ca channel antagonist
gp120/41 CD4
The FasL/Fas (CD95) ligand/receptor complex helps maintain lymphocyte homeostasis via cell depletion
HIV-induced Apoptosis via Fas Receptor
Fas/FasL Mechanism of Action
CAD (caspase-activatable DNase)
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)
Observation: uninfected T-cells from HIV+ Patients
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
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