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PATHOGENESIS OF AIDShow does HIV cause AIDS?

Neal Nathanson, MDEmeritus Professor

Department of MicrobiologyUniversity of Pennsylvania

School of Medicine

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

DefinitionsStructure of HIVHIV entry and cell tropismHIV-cell interactionsCourse of HIV infection and AIDSHIV variants during infectionHIV persistenceHow does HIV cause immunodeficiency?

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

DEFINITIONS

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

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

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

STRUCTURE OF HIV

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PATHOGENESIS OF AIDShow 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 AIDShow does HIV cause AIDS?

The genes of HIV in the virion (RNA) and integrated into host cell genome (DNA)

STRUCTURAL GENES

AUXILIARY GENES

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HIV ENTRY INTO CELLSAND CELL TROPISM

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HIV attaches to cells in two stepsSTEP 1 HIV attaches to its primary receptor, CD4STEP 2 HIV attaches to a co-receptor, either CCR5 or CXCR4

STEP 1 STEP 2

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HIV infects cells that carry the receptor and co-receptorCD4 Expressed on the surface of CD4 T lymphocytes (helper T

lymphocytes) and macrophages (including dendritic cells)

CCR5 Expressed on CD4+ T lymphocytes and on macrophagesCXCR4 Expressed on CD4+ T lymphocytes and T cell lines

R5 VIRUSES X4 VIRUSES

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HIV-CELL INTERACTIONS

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

0 10 20 30

p24

ANTI

GEN

(LO

G N

G/M

L)

-2

-1

0

1

2

3

MACROPHAGE-TROPIC VIRUS (SF162)TCL-ADAPTED VIRUS (IIIB)

PERIPHERAL BLOOD LYMPHOCYTES

INFECTED CELLS DIE

0 10 20 30

-2

-1

0

1

2

3MONOCYTE-DERIVED MACROPHAGES

NEGATIVE

INFECTED CELLS SURVIVE

HIV infection of cultured cells shows (Collman, 1989)

both R5 and X4 viruses infect and kill CD4 T lymphocytes

Only R5 viruses infect macrophages and they are not killed

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

COURSE OF HIV INFECTION AND AIDS

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HOW HIV INITIATES HETEROSEXUAL INFECTION (Shattock, 2003)

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

THE COURSE OF HIV INFECTION AND AIDS (After Fauci, 1993)

YEARS AFTER INFECTION0 0.06 0.12 0.18 0.23 1 2 4 6 8 10

HIV

RN

A (L

OG

10 C

OPI

ES P

ER M

L)

0

1

2

3

4

5

6

7

1000

800

600

400

200

0

PRIMARY INFECTION CLINICAL LATENCY

AIDSOPPORTUNISTICINFECTIONS

CD

4 T

CEL

LS P

ER µ

L

CD4 COUNT

HIV RNA

1200

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HIV VIREMIA BY STAGE OF HIV INFECTION (Bagasra, 1993; Pan, 1993)

STAGE OF INFECTIONCD4

CELL COUNT

PLASMA HIV (TCID PER ML)

% CD4+ CELLS

INFECTED

ASYMPTOMATIC

GENERAL LYMPHADENOPATHY

CLINICAL AIDS

>500

300-499200-299

<200

100

200400

1,500

3%

20%

30%

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HIV VARIANTS DURING INFECTION

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

VIRUS VARIATION IS OFTEN SEEN DURING THE COURSE OF HIV INFECTION

VIRUS ISOLATED FROM PATIENTS WITHBIOLOGICAL

PHENOTYPE ASYMPTOMATIC EARLY INFECTION AIDS

REPLICATION KINETICS

SYNCYTIUM INDUCTION

CELLULAR HOST RANGE

CO-RECEPTOR USAGE

SLOW/LOW

NON SI

DUO-TROPIC

R5

HIGH/RAPID

SI

T CELL-TROPIC

X4

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

DIFFERENTIAL INFECTION OF MONKEYS BY CO-RECEPTOR USAGE (Harouse, 1999)

0 6 12 18 24 30 36 42 48VIR

EMIA

(RN

A C

OPI

ES P

ER M

L)

3

4

5

6

7

3

4

5

6

7

WEEKS AFTER INFECTION

0 6 12 18 24 30 36 42 48

CD

4:C

D8

RA

TIO

0.0

0.5

1.0

1.5

2.0

0.0

0.5

1.0

1.5

2.0

MACROPHAGE-TROPICSHIV SF162PLPL DEPLETED

LYMPHOCYTE-TROPICSHIV SF33ALN DEPLETED

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

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

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HIV PERSISTENCE

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PATHOGENESIS OF AIDShow 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)

13

2

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

ANTI-RETROVIRAL TREATMENT REFLECTS THE THREE HIV IN VIVO INFECTION CYCLES(Mittler, 1999; and others)

DAYS AFTER BEGINNING HAART0 20 40 60 80

DEC

REA

SE IN

VIR

EMIA

LOG

10 H

IV R

NA

-3

-2

-1

0

t 1/2 ~1 days

t 1/2 ~ 14 days

sensitivity

INFECTED T LYMPHOCYTES (1)

INFECTED MACROPHAGES (2)

LATENTLYINFECTED T CELLS (3)

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PATHOGENESIS OF AIDShow does HIV cause AIDS?

HOW DOES HIV CAUSE IMMUNODEFICIENCY?

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PATHOGENESIS OF AIDShow 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 AIDShow does HIV cause AIDS?

Still an enigma?

from THE SCIENTIST, 2003

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