Rapporteur Session Track A

1
Rapporteur SessionTrack A

• Rafick-Pierre Sekaly
• Toronto
• August 18th 2006

2
Rapporteur Team

• Committed , talented , present
• Nicole Bernard ( MUCH )
• Alan Cochrane ( University of Toronto)
• Michel Tremblay ( CR-CHUL )
• Rupert Kaul ( UHN )
• Keith Fowke ( University of Manitoba)

3
Theme 1Immune Activation Driving HIV Disease
Progression and Susceptibility to Infection
4
Meier

• HIV has regions that stimulate the innate immune
  system through TLR 7/8 receptors and can lead to
  chronic immune activation

5
Additional HIV-1 derived TLR ligands activate
CD8 T cells
6
T.B. Ball

• PBMC from HEPS women show greater sensitivity to
  TLR stimulation by producing more
  immunosuppressive IL-10 and less immune
  stimulatory IFN-gamma

7
HIV resistant women have elevated IL-10,
depressed IFN-? to TLR7 stimulation
Res, HR neg, LR neg
Res, HR neg, LR neg
8
Barbercheck

• African green monkeys have non-pathogenic SIV
  infections and have higher amount of regulatory T
  cells

9
High Number of Tregs Relative to Low Numbers of
CD4 T Cells in AGMs
10
Barre-Sinoussi

• Role of anti-inflammatory cytokines in AGM vs
  Rhesus

11
Correlation between an early balance in favor of
anti-inflammatory profiles and protection against
AIDS.
HIV
SIVsm/mac
African SIVs
HIC/LTNP
AIDS
Resistance to AIDS
Inflammation
Th2/anti-inflammatory
Th2/anti-inflammatory
Early TGF-?, FoxP3 and IL-10, IFN-???Smad4
Th1
Generalized T cell Activation
anti-inflammatory/Treg
M.Muller-Trutwin et al. others
12
Future HIV vaccine strategies based on novel and
creative scientific concepts

• A vaccine candidate targeting both the infection
  and the very early pathogenic signals in response
  to HIV infection in effector sites (including
  mucosa)
• associated or not to
• novel therapy or to gene silencing
• ????

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Theme 2Development of HIV Vaccines
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Costimulation of T cell Responses circa 1990
APC

B7.1 or B7.2
4-1BBL
CD28


4-1BB
T cell

• IL-2
• Survival
• Bcl-XL

15
Quantitative expansion of viral-specific memory
CD8 T cells
No Ag
cAdV
4-1BBL
LIGHT
CD70
influenza- specific CD8
16
SIV Gag
HIV Env.
peptides
peptides
1.4
Group/PBS
0
1
2
3
4
10
10
10
10
10
3.1
FL1-H
SHIV VLP 20 µg
0
1
2
3
4
10
10
10
10
10
4.4
FL1-H
SHIV VLP 100 µg
4.7
FL1-H
mCD40L/SHIV
VLP 20 µg
IFN-?
mCD40L/SHIV
7.4
FL1-H
VLP 100 µg
0
1
2
3
10
10
10
10
FL1-H
CD8
17
Blocking the activity of anti-HIV factors
?-IL-27
?-IL-27
VLP stimulated anti-HIV activity is partially
blocked by ?-IL-27
18
Construction of Ad virus
Ad5 virus Ad5/35 virus
Chimeric Ad5/35 fiber
Ad35 fiber knob Ad35 fiber shaft Ad5 fiber
tail Ad5 penton base
19
Time course studies of viral RNA copies after
SHIV89.6 challenge
1010 109 108 107 106 105 104 103
Control
DNA-HIV(2x)
Serum virus titer(RNA cope/ml)
1010 109 108 107 106 105 104 103
1010 109 108 107 106 105 104 103
DNA-HIV(2x)
Ad5/35-HIV(1x) Ad5/35-HIV (1x)
Weeks
20
HSV2 may drive HIV transmission

• In regions of high HSV2 seroprevalance
• Mathematical modeling predicts 50 of new HIV
  cases directly attributed to HSV2

21
Impact of HSV2 status on FGT immune milieu
Lymphocyte Populations
22
One possible model for mucosal HIV-HSV2 synergy
HSV2 infection
23
Preservation of a subset of T cells with central
memory markers in infected macaques controlling
viremia a correlate of vaccine induced protection
Naïve
WT (wk 19 PI)
naive
effector
CD45RA
CD45RA
central memory
8.2
37.4
CD28
ART/DNA(70 wks post-ART)
att.SIV (yr 6 PI)
att. SIV challenge (yr 4.5 PC)
CD45RA
36.2
36.5
21.6
CD28
CD28
CD28
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Theme 3Viral Determinants
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Viral Determinants of Fitness/Disease Progression

• Characteristics of env associated with rapid
  progression (increased glycosylation in V1/V2
  region) (Bandawe et al.).
• Virus mutates to escape immune pressure and
  increase fitness following transmission. Viral
  fitness increases with time, rapid progressors
  have virus of greater fitness than LTNPs. Changes
  in Gag to escape CTL response reduces viral
  fitness (E. Arts).
• Proportion of X4 versus R5 virus predicts
  response to ART and progression to AIDS/death

26
Conclusions
27
Does CTL escape mutations correspond to other
clinical parameters?
Conclusions CTL escape mutations in gag epitopes
reduce fitness and appear later in infection CTL
escape mutations in env emerge early but without
a significant cost in fitness The env gene is
major target for both CTL and humoral
activity Furthermore, in untreated patients,
replicative fitness maps to the env gene and is
controlled by the efficiency of host cell entry
28
Kaplan-Meier Estimates of the Probability of
Progression to AIDS or Death Stratified
According to Viral Phenotype (R5 versus X4)
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Impact of HIV on the Host Cell

• Vpr-induced apoptosis of T cells (Zimmerman et
  al.), and neurons (Barsby et al.)
• HIV-induced changes in host gene expression.

30
HIV uses a viral decoy RNA to suppress the
cells RNAi defense
31
HIV alters the cells miRNA profile
no signal
Low signal
High signal
32
Alternation of Host Gene Expression Upon
Exposure To HIV-1
33
THANK YOU

• This was a great meeting