PATHOGENESIS OF AIDS

how does HIV cause AIDS?

Neal Nathanson, MD Emeritus Professor Department of Microbiology University of Pennsylvania School of Medicine

PATHOGENESIS OF AIDS
how does HIV cause AIDS?

Definitions Structure of HIV HIV entry and cell tropism HIV-cell interactions Course of HIV infection and AIDS HIV variants during infection HIV persistence How does HIV cause immunodeficiency?
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PATHOGENESIS OF AIDS
how does HIV cause AIDS?

DEFINITIONS HIV: human immunodeficiency virus

HIV is a member of the lentivirus family, a subgroup of retroviruses, RNA viruses that replicate via a DNA intermediate

AIDS: acquired immunodeficiency syndrome

AIDS is defined by a loss of CD4 T lymphocytes or the occurrence of opportunistic infections or cancers

PATHOGENESIS OF AIDS
how does HIV cause AIDS?

STRUCTURE OF HIV

PATHOGENESIS OF AIDS
how does HIV cause AIDS?
A diagram of the virus particle to show the internal structure (after Brooks et al, 1998)

VIRUS SPIKE CONSISTING OF TWO ENVELOPE PROTEINS gp120 and gp 41 VIRUS ENVELOPE (LIPID BILAYER)

VIRUS CAPSID CONTAINING THE RNA GENOME

PATHOGENESIS OF AIDS
how does HIV cause AIDS?
The genes of HIV in the virion (RNA) and integrated into host cell genome (DNA)

AUXILIARY GENES

STRUCTURAL GENES

PATHOGENESIS OF AIDS
how does HIV cause AIDS?

HIV ENTRY INTO CELLS AND CELL TROPISM

PATHOGENESIS OF AIDS
how does HIV cause AIDS?
HIV attaches to cells in two steps STEP 1 HIV attaches to its primary receptor, CD4 STEP 2 HIV attaches to a co-receptor, either CCR5 or CXCR4

STEP 1

STEP 2

PATHOGENESIS OF AIDS
how does HIV cause AIDS?
HIV infects cells that carry the receptor and co-receptor CD4 Expressed on the surface of CD4 T lymphocytes (helper T lymphocytes) and macrophages (including dendritic cells) CCR5 CXCR4 Expressed on CD4+ T lymphocytes and on macrophages Expressed on CD4+ T lymphocytes and T cell lines
R5 VIRUSES X4 VIRUSES

PATHOGENESIS OF AIDS
how does HIV cause AIDS?

HIV-CELL INTERACTIONS

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
HIV infection of cultured cells shows (Collman, 1989)
PERIPHERAL BLOOD LYMPHOCYTES p24 ANTIGEN (LOG NG/ML)

3 2 1 0 -1 -2 0 10 20 30
MACROPHAGE-TROPIC VIRUS (SF162) TCL-ADAPTED VIRUS (IIIB)

both R5 and X4 viruses infect and kill CD4 T lymphocytes

INFECTED CELLS DIE

MONOCYTE-DERIVED MACROPHAGES

3 2

Only R5 viruses infect macrophages and they are not killed

1 0 -1

INFECTED CELLS SURVIVE

NEGATIVE

-2 0 10 20 30

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?

COURSE OF HIV INFECTION AND AIDS

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
HOW HIV INITIATES HETEROSEXUAL INFECTION (Shattock, 2003)

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
THE COURSE OF HIV INFECTION AND AIDS (After Fauci, 1993)
AIDS OPPORTUNISTIC INFECTIONS

PRIMARY INFECTION

CLINICAL LATENCY

HIV RNA (LOG10 COPIES PER ML)

7 6 5 HIV RNA 4 3 2 1 0 0 0.06 0.12 0.18 0.23 1 2 4 6 8 10 YEARS AFTER INFECTION CD4 COUNT 800 600 400 200 0 1200 CD4 T CELLS PER L 1000

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
HIV VIREMIA BY STAGE OF HIV INFECTION (Bagasra, 1993; Pan, 1993)

STAGE OF INFECTION

CD4 CELL COUNT >500 300-499 200-299 <200

PLASMA HIV (TCID PER ML) 100 200 400 1,500

% CD4+ CELLS INFECTED 3% 20%

ASYMPTOMATIC GENERAL LYMPHADENOPATHY CLINICAL AIDS

30%

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?

HIV VARIANTS DURING INFECTION

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
VIRUS VARIATION IS OFTEN SEEN DURING THE COURSE OF HIV INFECTION VIRUS ISOLATED FROM PATIENTS WITH ASYMPTOMATIC EARLY INFECTION SLOW/LOW AIDS HIGH/RAPID

BIOLOGICAL PHENOTYPE

REPLICATION KINETICS SYNCYTIUM INDUCTION CELLULAR HOST RANGE CO-RECEPTOR USAGE

NON SI

SI

DUO-TROPIC

T CELL-TROPIC

R5

X4 17

PATHOGENESIS OF AIDS
how does HIV cause AIDS?
DIFFERENTIAL INFECTION OF MONKEYS BY CO-RECEPTOR USAGE (Harouse, 1999)

MACROPHAGE-TROPIC SHIV SF162P LPL DEPLETED

MACROPHAGE-TROPIC (R5) SHIV INFECTS GUT-ASSOCIATED LYMPHOID TISSUE PREFERENTIALLY WITH MODEST REDUCTION OF CD4 CELLS IN CIRCULATION

VIREMIA (RNA COPIES PER ML)

7 6 5 4 3
0 6 12

LYMPHOCYTE-TROPIC SHIV SF33A LN DEPLETED

7 6 5 4 3

18

24

30

36

42

48

2.0

2.0 1.5 1.0 0.5 0.0

0 6 12 18 24 30 36 42 48

T CELL-TROPIC (X5) SHIV INFECTS LYMPH NODES PREFERENTIALLY WITH SEVERE REDUCTION OF CIRCULATING CD4 CELLS

CD4:CD8 RATIO

1.5 1.0 0.5 0.0

WEEKS AFTER INFECTION

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?

HIV PERSISTENCE

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
HIV INFECTION IN VIVO INCLUDES (Ho, 1999) Replication in activated T lymphocytes (1) Replication in macrophages (2) Latency in resting lymphocytes (3)

1
2

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
ANTI-RETROVIRAL TREATMENT REFLECTS THE THREE HIV IN VIVO INFECTION CYCLES (Mittler, 1999; and others)

DECREASE IN VIREMIA LOG10 HIV RNA

-1

INFECTED T LYMPHOCYTES (1) t 1/2 ~1 days INFECTED MACROPHAGES (2)

t 1/2 ~ 14 days
sensitivity

-2

-3 0 20 40

LATENTLY INFECTED T CELLS (3)

60

80

DAYS AFTER BEGINNING HAART

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?

HOW DOES HIV CAUSE IMMUNODEFICIENCY?

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PATHOGENESIS OF AIDS
how does HIV cause AIDS? CD4 AND CD8 T LYMPHOCYTES: A CENTRAL PARADOX IN THE PATHOGENESIS OF AIDS

Opportunistic infections are mainly due to the activation of existing latent infections Control of latent infections is mediated by parasite-specific CD8 effector T lymphocytes, which are NOT the direct target of HIV Indirect mechanisms must be responsible for the depletion of effector CD8 cells, including

Hyperactivation of T cells leading to apoptosis and premature cell death

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PATHOGENESIS OF AIDS
how does HIV cause AIDS?
Still an enigma?

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from THE SCIENTIST, 2003

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