PATHOGENESIS OF AIDS how does HIV cause AIDS?
Neal Nathanson, MD Emeritus Professor Department of Microbiology University of Pennsylvania School of Medicine
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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? 2
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
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PATHOGENESIS OF AIDS how does HIV cause AIDS?
STRUCTURE OF HIV
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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
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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
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PATHOGENESIS OF AIDS how does HIV cause AIDS?
HIV ENTRY INTO CELLS AND CELL TROPISM
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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
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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
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PATHOGENESIS OF AIDS how does HIV cause AIDS?
HIV-CELL INTERACTIONS
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PATHOGENESIS OF AIDS how does HIV cause AIDS?
both R5 and X4 viruses infect and kill CD4 T lymphocytes
PERIPHERAL BLOOD LYMPHOCYTES p24 ANTIGEN (LOG NG/ML)
HIV infection of cultured cells shows (Collman, 1989)
3 2
INFECTED CELLS DIE
1 MACROPHAGE-TROPIC VIRUS (SF162) TCL-ADAPTED VIRUS (IIIB)
0 -1 -2 0
10
20
30
MONOCYTE-DERIVED MACROPHAGES
3 2
Only R5 viruses infect macrophages and they are not killed
1
INFECTED CELLS SURVIVE
0 -1 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)
CLINICAL LATENCY
7 6
1200
5
1000 HIV RNA
4
800
3
600
2
400 CD4 COUNT
1
200
0
CD4 T CELLS PER µL
HIV RNA (LOG10 COPIES PER ML)
PRIMARY INFECTION
AIDS OPPORTUNISTIC INFECTIONS
0 0
0.06 0.12 0.18 0.23
1
2
4
YEARS AFTER INFECTION
6
8
10
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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
ASYMPTOMATIC GENERAL LYMPHADENOPATHY CLINICAL AIDS
CD4 CELL COUNT
PLASMA HIV (TCID PER ML)
% CD4+ CELLS INFECTED
>500
100
3%
300-499 200-299
200 400
20%
<200
1,500
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
BIOLOGICAL PHENOTYPE
REPLICATION KINETICS SYNCYTIUM INDUCTION CELLULAR HOST RANGE CO-RECEPTOR USAGE
VIRUS ISOLATED FROM PATIENTS WITH ASYMPTOMATIC EARLY INFECTION
AIDS
SLOW/LOW
HIGH/RAPID
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)
T CELL-TROPIC (X5) SHIV INFECTS LYMPH NODES PREFERENTIALLY WITH SEVERE REDUCTION OF CIRCULATING CD4 CELLS
CD4:CD8 RATIO
MACROPHAGE-TROPIC (R5) SHIV INFECTS GUT-ASSOCIATED LYMPHOID TISSUE PREFERENTIALLY WITH MODEST REDUCTION OF CD4 CELLS IN CIRCULATION
VIREMIA (RNA COPIES PER ML)
MACROPHAGE-TROPIC SHIV SF162P LPL DEPLETED
LYMPHOCYTE-TROPIC SHIV SF33A LN DEPLETED
7
7
6
6
5
5
4
4
3
3 0
6
12
18
24
30
36
42
48
2.0
2.0
1.5
1.5
1.0
1.0
0.5
0.5
0.0
0.0 0
6
12
18
24
30
36
42
48
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)
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
0
INFECTED T LYMPHOCYTES (1) t 1/2 ~1 days
-1
INFECTED MACROPHAGES (2)
-2
t 1/2 ~ 14 days
LATENTLY INFECTED T CELLS (3)
sensitivity -3 0
20
40
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 23
PATHOGENESIS OF AIDS how does HIV cause AIDS? Still an enigma?
24 from THE SCIENTIST, 2003
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