2. 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

3. 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

4. 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

6.  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:

7. Causes of deaths, globally and in Africa 4.2 2.8 2.3 19 2.2 0.3 0 2 4 6 8 10 12 14 16 18 20 HIV/AIDSTuberculosisLung cancer Percent of deaths Global Africa

8. Projected changes in life expectancy in selected African countries with high HIV prevalence, 1995–2000 Source: United Nations Population Division, 1996 1955196019651970197519801985199019952000 Average life expectancy at birth, in years 65 60 55 50 45 40 35 Zimbabwe Zambia Uganda Botswana Malawi

9. HIV prevalence rate among teenagers in Kisumu, Kenya, by age 00 3.6 2.2 8.6 8.3 17.9 29.4 22 33.3 0 5 10 15 20 25 30 35 1516171819 Age in years HIV prevalence (%) boys girls Source: National AIDS Programme, Kenya, and Population Council, 1999

10. 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...

11. CO-OPTION AND DESTRUCTION OF THE IMMUNE SYSTEM BY HIV

12. OVERVIEW OF THE HIV LIFECYCLE

14. CLINICAL COURSE OF HIV INFECTION

15. 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

16. CD4 - cells can be infected by HIV e.g.: Bowel/Renal epithelia ALTERNATIVE RECEPTORS FOR HIV (CD4-INDEPENDENT)

17. 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 (1) GalC - Galactosyl ceramide

18. 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 (2) Pseudotype Viruses in HIV Infection HIVHSV CELL pseudotypes

19. 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 DIRECT TOXIC EFFECTS OF HIV PROTEINS (b) Cultured brain cells exposed to gp120 show an influx of Ca 2+  overactivation of Ca 2+ Kinases etc.  Reversed by nimodipine - Ca channel antagonist gp120/41 CD4

20. The FasL/Fas (CD95) ligand/receptor complex helps maintain lymphocyte homeostasis via cell depletion HIV-induced Apoptosis via Fas Receptor

21. Fas/FasL Mechanism of Action CAD (caspase-activatable DNase)

22.  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

23.  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