Date post: | 17-Oct-2014 |
Category: |
Documents |
Upload: | national-press-foundation |
View: | 280 times |
Download: | 0 times |
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?
0
40000
80000
120000
160000
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