Hong Kong Aids 2003

8/6/2019 Hong Kong Aids 2003

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Sir Edward Youde Visiting Professor

Public Lecture

The HIV Pandemic

Andrew McMichaelMRC Human Immunology Unit

Weatherall Institute of Molecular Medicine

University of Oxford


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WesternEurope

560560

000000North Africa& MiddleEast

440 000440 000Sub-

SaharanAfrica

28.128.1millionmillion

EasternEurope& Central Asia

1 million1 million

South& South-East

Asia 6.16.1millionmillionAustralia

& NewZealand

15 00015 000

NorthAmerica

940940

000000Caribbean

420420000000Latin

America

1.41.4millionmillion

Total: 40 million

East Asia &Pacific

1 million1 million

Adults and children estimated to be livingAdults and children estimated to be living

with HIV/AIDS as of end 2001with HIV/AIDS as of end 2001


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Origins of HIV?


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C

C

C

E

BB

BA,D

E

C

C

C

B

BB

2

A-HO, N

B

Strains / Clades

Clades differ by around 20% of RNA and Protein sequence


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AIDS in Africa

3.5 million new infections in Africa each year


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Changes in life expectancy in selected Africancountries with high HIV prevalence

Changes in life expectancy in selected Africancountries with high HIV prevalence

Source:Source: United Nations Population Division,United Nations Population Division,

19961996

Source:Source: United Nations Population Division,United Nations Population Division,

19961996

19519555

19519555

19619600

19619600

19619655

19619655

19719700

19719700

19719755

19719755

19819800

19819800

19819855

19819855

19919900

19919900

19919955

19919955

20020000

20020000

Average life expectancy at birth, in yearsAverage life expectancy at birth, in yearsAverage life expectancy at birth, in yearsAverage life expectancy at birth, in years6565

6060

5555

5050

4545

4040

3535

6565

6060

5555

5050

4545

4040

3535

ZimbabwZimbabweeZimbabwZimbabweeZambiaZambiaZambiaZambia

UgandUgand

aa

UgandUgand

aa

BotswanBotswanaaBotswanBotswanaa

MalawiMalawiMalawiMalawi

World HealthOrganizationWorld HealthOrganization

projectionsprojections


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Binding of gp 120 to CD4 and CCR5


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CD4 & CCR5


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Killer T cellsCD8 positive

T helper cells

CD4 positive

B cells

antibody

cytokines

cytokines

Antigen


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Killer T cellsCD8 positive

T helper cells

CD4 positive

B cells

antibody

cytokines

cytokines

Antigen

P th i f AIDS


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Pathogenesis of AIDS

Direct infection of CD4 T cells, macrophages and dendritic cells

Cytopathic to infected cells

Hyperactivation of immune response: T cells and B cells

Activation induced cell death of uninfected T cells

Preferential infection and loss of HIV specific T cells

Viral persistence despite immune response: escape

Breakdown of all T cell immune responses

CD4 T cell

B

CD8 T

HIV specific

CD4 T

CD4 T

DC


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The Immune Response to HIV

Virus load

CTL

N Ab

Acute infection

6 - 12 weeks

Asymptomatic period

1 - 15 years

AIDS

2 - 3 years

CD4 T cells


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HIV Envelope (Gp 120) Structure:

From Wyatt et al, Nature 393, 705-711, 1998

Neutralising antibodies:

CD4 binding site: needs

very long VH CDR3

CD4 inducible; needsFab

Mannose: needs crossed-

over antibody

NAb in infection rapidly

select escape mutants


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Infection Antigen presentation Virus release Cytopathicity

O 12 hours 24 hours 1-2 days

QuickTime and aCinepak decompressor

are needed to see this picture.

Video by

Xiaoning Xu


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Protein

ubiquinated

proteasome

peptides

TAP transporter

Class I molecule + chaperones

Surface HLA class I molecule

plus peptide

Cytosol

Endoplasmic

Reticulum


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V17 T ll t


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V17 T cell receptor

binding to HLA A2 +

GILGFVFTL

R98

D32


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HLA-B27-restricted gag-specificCTL in primary HIV infection -

donor SC40

100

1000

10000

100000

1000000

10000000

0

1

2

3

%

B27-G

agstaining

0 100 200 300 400

Days post HIV infection

Wilson et al 2000

HIV t ti h CTL


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HIV escape mutations when CTL response

focused on dominant epitope

HLA HIV gene Sequence Effect Authors

B27 gag p24 KRWII LGLNK Phillips et al

KKWIIMGLNK No binding Goulder et al

KTWIIMGLNK Kelleher et

KGWII LGLNK

B44 env AENLWVTVY

AXNLWVTVY No binding Borrow et al

B8 nef FLKEKGGL

FLKEXGGL No binding Price et al

.. deleted


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Escape by one amino acid change

in p24 gag

CD4 Count

%R2%K2

KRWIIMGLNK

KKWIIMGLNK


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No. B27+HIV+

R264K L268M S173A

R264T

R264G

26 10 10 85 5 0

2 0 0

No. B27-HIV+

19 0 0 0 0 0

KRWIILGLNK

The triple change may account for slow escape

this epitope and possibly protective effect of

HLA B27 Kelleher et al 2003


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Immune Control of HIV

Virus load (Log)

CTL

N Ab

Acute infection

6 - 12 weeks

Asymptomatic period

1 - 15 years

AIDS

2 - 3 years

EscapeImmune

response


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CD4+ T-cell responses to HIV

1. Weak proliferative CD4+ T-cell responses to HIV

and other recall antigens in vitro; but fairly good

responses measured in short term culture

2. Long term slow progressors make proliferative CD4+

T-cell responses to gag;

Proliferative T cell responses can be rescued by earlyHAART. (Rosenberg et al 1998)

3. HIV preferentially infects HIV specific CD4 T cells

(Douek et al 2002)


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Help for CD8+ T cells?

1. Essential for initiation of CD8+ T cell response?

2. Maintain CD8+ T cell memory

3. Essential for CD8+ T cell function (cytokine

production and perforin mediated killing)?

HIV specific CD4+ T cell responses are impaired


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Options for the control of HIV

Education Drugs Vaccines

Mother to

Baby

Adults


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The Immune Response to HIV

Virus load

CTL

N Ab

Acute infection

6 - 12 weeks

Asymptomatic period

1 - 15 years

AIDS

2 - 3 years

CD4 T cells


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Types of HIV Vaccine

Traditional Example Type of immunity Status

Live attenuated virus D-Nef SIV Antibody and T cell Too Risky

Killed virus Remune Antibody only Dropped

Subunit Vaxgen gp120 Antibody Does not work


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The Ideal Vaccine

Neutralising

Antibody

T cell

Immunity

Mucosal

Immunity

Innate

Immunity


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Types of HIV Vaccine

Novel - stimulating T cell immunity

DNA Several in trial T cell Phase I/II

Recombinant virus Canarypox T cell Phase I

Adenovirus (Merck) T cell Phase I/II

MVA T cell Phase I/II

Prime-Boost DNA + MVA etc T cell Phase I/II


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HOW GENE-BASED VACCINES WORK

Plasmid or virus vector

i.m. or i.d.

Langerhans, muscle or other cell

translates gene, processes & presents immunogen

in MHC peptide complex

T cell recognition and activation

CTL kills inoculated cells

Memory T cells


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V i th t ti l t Kill T ll


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Barouch et al DNA + IL-2

Amara et al DNA + rMVA

Shiver et al DNA/rAdV

Rose et al rVSV

Vaccines that stimulate Killer T cells

protect rhesus monkeys against

SIV/SHIV infection:

Consistent reduction of virus load

by 100-1000 fold after challenge

with virus

Note SIV challenge is 10-100 times human infecting dose:

Nairobi Sex Workers take >100 contacts before half are infected


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Pumwami Sex Workers90% HIV infected

5% resistant to HIV infection for >3 years

Make killer T cell responses to HIV

Can T cell Immunity protect against HIV infection??

l d d i d


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HIV-1 gag CTL epitopes

p24

macaque epitope

mouse epitope mAb epitope

p17

pol

env

nef

HIV clade A-derived Immunogen - HIVA

-10

0

10

20

30

40

50

60

70

50 2 5 12 6 350 2 5 12 6 3

1x DNA i.m. 2x DNA g.g.

Effector:Target Ratio

100 50 25 12

0

10

20

30

40

50

60

-10

70

1x MVA i.m.

Effector:Target Ratio

DNA immunisation MVA immunisation


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Induction of CTL:in Mamu *A01+ Macaques

DNA prime 8ug gene gun x2 id

MVA boost 5x108 pfu x 2 id


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C

C

C

E

BB

BA,D E

C

C

C

B

BB

2A-HO, N

B

Strains / Clades

Clades differ by around 20% of RNA and Protein sequence

Trials August 2000 October 2003


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Trials August 2000 - October 2003

4 Phase I trials completed in Oxford and Nairobi2 Phase I trials in progress in Nairobi

1 Phase II trial in progress in Oxford and London

1 Phase II trial in progress in Uganda1 Phase II trial in progress in Nairobi and London

5 more trials planned in 2003-2005 leading up to

Phase IIB proof of concept trial in East Africa

A


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No peptide

Pool 1

Pool 2

Pool 3

Pool 4

Pool 5

Pool 6

Pool 7

FEC

PHA

B

HIVA

p24 p17 Epitopes

Pool 1 Pool 2 Pool 3 Pool 4

Pool 5/Pool 6/Pool 7

Figure 1. Anti-HIV T cell responses. Mwau et al.

A


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No peptide

Pool 1

Pool 2

Pool 3

Pool 4

Pool 5

Pool 6

Pool 7

FEC

PHA

B

HIVA

p24 p17 Epitopes

Pool 1 Pool 2 Pool 3 Pool 4

Pool 5/Pool 6/Pool 7

Figure 1. Anti-HIV T cell responses. Mwau et al.


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Examples of Elispot Responses to HIVA Vaccine in

HIV negative Volunteers immunised with

DNA x2 then MVA on Day 0 and 21


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Vaccine Elispot Responses

(>4x background

> Mean + 2sd)

DNA 7/18

MVA 7/8

DNA + MVA 7/8

Provisional results, first phase I trials


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Early results in HIV negative lowHIV risk volunteers show

vaccines so far safe and stimulate T cellresponses in more thanhalf volunteers.

Current trials are optimising dose, route and combinations of

vaccines, aiming to stimulate responses in >75% vaccinerecipients

Then will move to trials in high risk volunteers in collaboration

with teams in Nairobi and Entebbe.

Trials sponsored by International AIDS Vaccine Initiative and

Medical Research Council


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Conclusions

Increasing understanding of how the immune response attempts

to control HIV infection and how HIV evades this

Attempts to make a vaccine have been so far unsuccessful usingtraditional approaches

Promising new approaches to prophylactic vaccines

Therapeutic vaccines may improve therapy

However, vaccines still several years away


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Tomas Hanke

Matilu MwauSandip Patel

Julian Sutton

Inese Cebere

Sarah Rowland-JonesVictor Appay

Tony Kelleher

Graham Ogg

Jean Lee

Tao Dong

Job Bwayo

Omu AnzalaDorothy Mbori-Ngacha

Bashir Farah

Julius Oyugi

K Bhatt

Documents

Hong Kong Aids 2003