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