hiv/aids and immunology (dr. marylyn addo)

The role of immune responses in HIV-1 Infection

Marylyn M. Addo, MD/PhD

Partners AIDS Research Center

Massachusetts General Hospital

Harvard Medical School

Boston, MA USA

Altfeld_CAP150_03

1000

800

600

400

200

1 5 10Time (years)Time (years)

CD

4 p

er m

mC

D4

per

mm

33

Natural History of HIV-1

VZVVZV

TBTB

Kaposi SarcomaKaposi Sarcoma

PCPPCP

15

CMV MAC Crypto LymphomaCMV MAC Crypto Lymphoma

symptomssymptoms

CD4CD4

HIV RNAHIV RNA

HIV

RN

A c

op

ies/

ml

HIV

RN

A c

op

ies/

ml

104

105

106

The level of HIV in the blood stream predicts subsequent survival

RN

A p

arti

cles

/ml

pla

sma

One year

Rapid Progression

Slow Progression

Viral set point

What influences viral load in HIV infection?

Viruses are not able to reproduce on their own

New virusassembly

2-3 Days

Viral set point is determined

by number of viruses produced by infected cells

Potential factors influencing the viral set

pointAttenuated virus

Host genetic factors

Host immuneresponse

Potential factors influencing the viral set

pointAttenuated virus

Host genetic factors

Host immuneresponse

HAARTHAART

New virusassembly

2-3 Days

Attenuated viruses

Example: Sidney blood bank cohortExample: Sidney blood bank cohort

Virus had a “mistake” in the nef geneVirus had a “mistake” in the nef gene

Attenuated viruses

Host genetic factors

CD4 CCR5

Co-receptor polymorphisms can prevent entry of virus into cells

32 base pair deletion in CCR5

B27 B57

Migueles, PNAS 97:2709, 2000

Some molecules on the cell of an individual are associated Some molecules on the cell of an individual are associated with improved viral control and slow disease progressionwith improved viral control and slow disease progression

Attenuated viruses

Host immune responses

Host genetic factors

New virusassembly

Humoral Immune System: Neutralizing Antibodies

B cell

New virusassembly

CTL

Solublefactors

Cellular immune Cellular immune system:system:

Killer T cellsKiller T cells

Cytotoxic T cellCytotoxic T cell

New virusassembly

CTL

Solublefactors

B cell

Th

Th

B cell

Th

Th

CTL

The Generals(T helper cells trained to target HIV)

Generals(T Helper cells)

Infantry(CTL)

EnemyInfected cell

Why are the generals absent in most infected persons?

Generals(T Helper cells)

Infantry(CTL)

EnemyInfected cell

Virus-Specific T Helper Cells:Essential for Maintenance of Effective CTL

Th cells absent Th cells present

Rel

ativ

e m

agn

itu

de

CTLViremia

ViremiaCTL

Is there any way to enhance the immune response against HIV?

Generals(T helper cells)

Infantry(CTL)

Enemy(Infected cells)

HAART

Generals(T Helper cells)

Infantry(CTL)

Enemy(Infected cell)

1

10

100

1000

0 20 40 60 80Ma

gn

itu

de

of

He

lpe

r C

ells

Effect of Early Treatment on the Generals

(HIV-Specific T Helper Cells)

Weeks on Treatment

What happens if you stop treatment?

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0 5 10 15 20 25 30 35 40

Weeks after first treatment interruption

vira

l lo

ad (

cop

ies

RN

A/m

L)

HAART

Early treatment of acute HIV infectionfollowed by treatment interruption

Very early treatment with HAART leads to enhanced natural control

of HIV

Where else do we find evidence for immune control in AIDS virus infection ?

In monkey studies, removing killer cells led to dramatic increases in viral load and restoring Killer T cells in those same monkey studies led to suppression of viral load

Individuals with high levels of Killer T cells have been shown to have low viral loads

Two interesting groups of individuals— HIV-1 long-term nonprogressors (LTNP)— HIV-1 exposed, but uninfected individuals (HEPS)

• Infected 21 years• Normal T cells• Undetectable viral load• Never on anti-HIV meds

LTNP

LTNP have strong and broadly directed killer cell responses and helper cell responses

HEPS Most well known:

— Nairobi sex worker cohort (Rowland-Jones et al.)

— Found killer T cell responses in these HEPS, that may contribute to protection from HIV

— Our group: collaboration with Lusaka, Zambia (PI: Susan Allen) studying killer cells in discordant couples and their partners

Poster session Poster session Thursday 12-2 pm (Addo)Thursday 12-2 pm (Addo)

Vaccine development Based on these pieces of data, it is felt that an

effective HIV-1 vaccine needs to elicit cellular

immune responses, in particular Killer T cell

responses +/- Helper T cell responses

Most recent and compelling data derive from

monkey studies demonstrating that Killer T

cell have an impact on vaccine efficacy in this

setting (Robbinson, Barouch/Letvin, Shiver)

Many vaccine approaches/trials currently in

study

Our current Research

Understanding of total the killer T cell and helper cell response against HIV, not only to single proteins like previous studies.

Analysis of the virus by sequencing

Bruce Walker morning Tuesday plenaryBruce Walker morning Tuesday plenary

Addo A05 Tuesday 14-15:30Addo A05 Tuesday 14-15:30

More research needed for other virus types and other ethnicities

Durban, RSA

Immune responses in Clade

C-Infection

Mother to child transmission

and pediatric treatment and

treatment interruption

studies

NIH contract Epitope

mapping in Non-Caucasians

Nelson Mandela School of MedicineUniversity of Natal

Lab

Why is HIV not controlled by the immune system like

other chronic viral infections?

Mono

Chicken pox

Herpes simplex

Problems

VIRAL ESCAPE

VIRAL DIVERSITY

How HIV mutates to escape Killer T-cells

Examples: Goulder et al, Nature 2001

— Viral escape mutants can be transmitted from mother to child

Barouch et al, Nature 2002— Loss of viral control in a vaccinated animal

associated with viral escape in one epitope

Viral escape

Viral DiversityComparing Viruses:

How much does HIV evolve compared to Flu?

Less Variation More Variation

Influenza variationcompared to HIV variation

1997-1998 Canadian Flu

1996 Global Flu

Influenza variationcompared to HIV variation

1990-1991Amsterdam

1997Dem Rep of Congo

1997-1998 Canadian Flu

1996 Global Flu

The extreme variability of HIV over time is a major impediment to immune control, effective drug therapy and vaccine development

Acknowledgements Marcus AltfeldMarcus Altfeld

Xu Yu Xu Yu

Almas RathodAlmas Rathod

Cecily FitzpatrickCecily Fitzpatrick

Paul LeePaul Lee

Philip GoulderPhilip Goulder

Christian BranderChristian Brander

Eric RosenbergEric Rosenberg

Bruce WalkerBruce Walker

Funding Sources:Funding Sources:

German Research Council (DFG)German Research Council (DFG)

amfARamfAR

Concerned Parents for AIDS Research (CPFA)Concerned Parents for AIDS Research (CPFA)

102

103

104

105

106

HLA-B27 is associated with slow progression to AIDS

ViralLoad

n = 10 HLA-B27+

HLA B27 molecule

I

W

K

I L

K

GL

The dominant CTL response in HLA-B27+ individuals:HIV Gag p24 KK10 epitope

LR

B27-KK10 escape is associated with elevated viral load

Non-controllers

p=0.025

All Arg/Lys at P2

102

103

104

105

106

Controllers

ViralLoad

HIV Gag p24 KK10 epitope

HLA B27 molecule

I

W

K

I L

K

GL

R L

KM

HLA B27 molecule

I

W

K

I L

K

GL

100%

80%

60%

40%

20%0%

n=21 86%

n=6 33%

p=0.02

PediatricAdult

2.73% CD8s

1.55% pbmc

IFN-

CD

8

B27-KK10 is recognized more frequently in adult than in pediatric HIV infection

B27-ve mother B27+ve mothers

2000

1600

1200

800

400

0

043-C

0 0 0

002-C 048-C 049-C

IFN-SFC/million PBMC

1925

B27-KK10 is not recognized in children of B27-positive mothers

2000

1600

1200

800

400

0

B27-ve mother B27+ve mothers043-C

0 0 0

002-C 048-C 049-C

B27-KK10 non-recognition associated with P2 anchor mutation

IFN-SFC/million PBMC

P2 anchormutationshared withmother

No P2 anchormutation