hiv and aids lecture

7/25/2019 HIV and AIDS Lecture

http://slidepdf.com/reader/full/hiv-and-aids-lecture 1/22

01/11/201

Ariberto Fassati

What is AIDS?Acquired ImmunoDeficiency Syndrome

First reported in 1981 in 5 North American gay menwww.cdc.gov/mmwr/PDF/wk/mm5021.pdf

Virus first isolated in France and USA

Barre-Sinoussi F, et al. Science. 1983 220: 868-71

Popovic M, Science. 1984 May 4;224(4648):497-500

“CDC's definition of AIDS includes all HIV-infected people who havefewer than 200 CD4+ T cells per cubic millimeter of blood”

http://www.niaid.nih.gov/factsheets/hivinf.htm

And presents with:Profound immune deficiency, Opportunistic infections and Kaposi’s Sarcoma

Lymphadenopathy, wasting, fever, pneumonia.

Very low CD4+ T cells, high CD8+ T cells (inverted T4:T8 ratio)

Acute HIV-1 infection presents as:

Asymptomatic or fever, headache, tiredness, generalised swollen glands

http://www.cdc.gov/mmwr/PDF/wk/mm5021.pdf



http://www.cdc.gov/mmwr/PDF/wk/mm5021.pdf



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ChimpanzeeGorilla Sooty mangabey

SIVcpz SIVgor SIVsm

HIV-1 M HIV-1 O HIV-2

HIV/AIDS: how?

Phylogenetic tree of HIVs and SIVs Based on sequencing data



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/AIDS

Faria et al. Science 2014 346: 56.

Different dynamics of HIV-1 O and HIV-1 M



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HIV-1 variation and the pandemic

Clade B and recombinants thereof are

dominant in North and South America,

Western Europe and Australasia

Clades A and C and recombinants are

dominant in China, India, sub-Saharan

Africa and parts of Russia.

Consequences for1) Vaccine design

2) Diagnosis

3) Pathogenesis

Group N: discovered in 1998 in Cameroon (rare)

Group O: “outlier ” in West-Central Africa

Group M: “major ” worldwide

HIV-1 sequence variability



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Date of origin of HIV-1: around 1920

First virus isolate available to date: 1952 from Kinshasa (DR Congo)

First retrospective case of HIV-1 seroconversion (infection): 1959

in Kinshasa.

First 5 cases reported in 1981 in USA

(Gottlieb et al. 1981 N. Engl. J. Med 305: 1425)

Number of deaths directly due to AIDS to 2007: >24 million

Number of people infected with HIV-1 at 2008: ~32 million

HIV/AIDS: when?

HIV/AIDS: where?



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Samples (from 1960) recovered from hospital in Congo showed that the epidemic probably started

around 1908



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Faria et al. Science 2014 346: 56.

II. HIV Life cycle



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HIV-1 genome organization Approximately 9Kb



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The outer envelope of

HIV consists of a lipidbilayer with protruding

Env spikes

(heterotrimers of

SU3TM3). Inside the

envelope lie shells of

Gag proteins. In the

immature particle, Gag

itself forms a single

shell.

Structure of the mature HIV Structure of the mature HIV- -1 particle1 particle

In the mature particle, MA associates with the membrane, CA forms the

conical capsid, and NC coats the viral RNA genome. The core contains two

genomic RNA strands (plus strand), tRNALys3, and ~50 copies of each viral

enzyme (PR, RT, and IN). Cellular proteins are also incorporated eg

Cyclophilins

Li, S., C. P. Hill, W. I. Sundquist, and J. T. Finch. 2000.

Image reconstructions of helical assemblies of the HIV-1 CA protein. Nature 407:409-13.

Image Reconstruction of HIV-1 Cores



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Robert W. Doms et al. Genes Dev. 2000; 14: 2677-2688

Major co-receptors: chemokine receptor CCR5 and CXCR4. CCR5 is essential for virus

transmission in vivo, present on T-helper lymphocytes, macrophages, microglial cells.

CXCR4 used in the late phase of the infection.



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Reverse transcription:

The RNA genome (two +strands of RNA)

is converted into a double stranded DNA

molecule by reverse transcriptase (RT), a

viral enzyme.

R U5 PBS PPT U3 AAA 3’ 5’

tRNA

R

PBS PPT

R U5U3

R U5U3

DNA synthesis

RNase H

R U5 PBS PPT U3 AAA

R

DNA synthesis

R U5

PBS PPT U3 AAA

R

RNase H

R U5

PBS PPT U3 AAA

R

First strand transfer

PBS PPT

R U5U3

DNA synthesis

RNase H

R U5U3

R U5U3

R U5U3

R U5U3

Second strand transfer

DNA synthesis

Reverse Transcription



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Visualisation of HIV-1 inside an infected cell. The RTC/PIC travels along microtubules and is

a large structure composed of viral and cellular factors. Reverse transcription takes place within

this structure.

Two bases are removed from the

3’ end of both viral DNA strands

by integrase

Cellular DNA is cleaved by

Integrase leaving two 4bp

overhangs

The 3’ ends of viral DNA areJoined to the host DNA a few

bases apart

Gaps and mismatches are

Repaired by cellular enzymes

And a 4 bp duplication is

formed at the end of the provirus

Integration and generation of a provirus



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MLV

HIV

HTLV

MPMV

Protease

Changes in virion

morphology during maturation

III. HIV-1 infection



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HIV-1 cellular tropism defined by

receptor usage

R5X4

CD4

CCR5CXCR4

Dendritic,

Langerhans

Macrophage

Microglia

Activated/ naive

effector memory

CD4+ T

Astrocyte

?

R5 X4

1) HIV may be picked up by inter-digitating

DCs and Langerhans cells (DC-SIGN or

direct infection) and shuttled to the draining

lymph nodes

2) HIV may cross the epithelial barrier

via damage to epithelium from trauma or

co-infection with other agents and directly

infect Lamina Propria CD4+ target cells

3) HIV may be able to transcytose across the

epithelial monolayer of the ecto-cervix to

access Lamina Propria

Initial seeding leads to massive

dissemination to all lymphoid tissue within

3 weeks on infection



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The natural history of HIV

infection

Viral load (RNA)

Total CD4 T cells

HIV-specific CD8 T cells

HIV-specific neutralising antibody

Primary

Infection

(months)

0 1 2 1 2 3 4 5 6 7 8 9 10 11

Asymptomatic (clinical latency)

(years)

AIDS

HIV-specific CD4 T cells

Average time to AIDS ~10

years post infection

Acute phase (1-4 weeks),

Antibodies present after 4

weeks (diagnostic).

Neutralising Abs appear

later in the course of

infection.

Anti-HIV CD8 T-cells

detected ~2 weeks after

infection, contribute to

control viral replication

V. Antiretrovirals



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Lipodystrophy

Myopathy

Hepatotoxicity

Immunorestoration

Disease

Rashes

Side Effects

HIV-1 resistance to drugs



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Problems with antiretrovirals:

1) Latent reservoirs (memory T-cells, brain microglia).

Thus virus cannot be eradicated by therapy.

2) Emergence and spread of resistant mutants (even to

several drugs).

3) Toxicity and compliance

IV. Viral reservoirs and latency



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HIV cellular reservoirs

The major reservoirs of HIV-infected cells includes resting memory

T cells

Is a cure possible?

One case of cure known (“Berlin patient”)

The “cured baby” was not cured

Several cases of long term remission known

May depend on size of reservoir (the smaller the better)

and time of therapy. May need novel approaches.

hiv and aids lecture

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