State of the Sciences: Research Updates from the IAS Leadership Tuesday, December 8, 2015 Johns Hopkins Bloomberg School of Public Health

1. « Toward an HIV Cure: Learning from Viral
Control off-ART »
Françoise BARRÉ-SINOUSSI
Institut Pasteur, Paris
CFAR & IAS Seminar
Johns Hopkins University
Sommer Hall,
Bloomberg School of Public Health
Baltimore, December 8, 2015

2. Key scientific challenges and Priorities in HIV science
HIV Vaccine discovery Comorbidities on ART HIV Cure discovery
Still no correlates of
protection but
significant progresses
in HIV vaccine
research with new
perspectives since the
Thai trial in 2009..
HIV infection, a
chronic condition
on life long cART
but non AIDS
related
comorbidities
Persistent HIV
infection on HAART
is the main hurdle
science must tackle
to achieve an HIV
“Cure”
Better knowledge on HIV basic
science on latency, immunology
and pathogenesis
Novel Vaccine and
Therapeutic Strategies?

3. “Which kind of “HIV Cure” are we looking for?
Elimination of all latently
infected cells
Persistent reduction and control:
Long term health without cART
and without risk to transmit
HIV Reservoirs on cART….
Berlin Patient? Proof of concept…
Cure
cART free
sustainable
Remission
Better
definition/
communication?

4. Cases of “Remission” post-very early treatment
ANRS EP 47 VISCONTI: 20 HIV+ patients (5-15%) treated at about 10w PI for 3
years, ≈10 years off treatment (no favorable HLA, no efficient CD8T cell
response, small reservoirs; very weak T cell activation)
VISCONTI Like teenager: ART at birth; at least 12 years in remission..…
Cases of Natural Control
SIV infected African NHP: active replication in blood but low reservoirs in LN
and attenuated inflammation/immune activation related to no gut destruction,
no microbial translocation and peculiar very early innate response (IFN-I, ISG,
strong NK activation…)
HIV Controllers: <0.3% of HIV+ people, no cART, natural control of HIV
infection (cell restriction to HIV, lower T cell activation, HLA B57/B27, efficient
CD8T cell response related to NK cell activation)
Why do we are optimistic about at least cART free
disease remission?

5. What can we learn from post-treatment controllers
(PTC) ?
« Patients in remission? ». Why?
ANRS VISCONTI study: 14 PTCs
Start cART: median 39 days p.i.
Months on cART : median 3 years
Months post-cART: > 10 years
cART
START STOP
viremia
years>1 year
756
cART
1013
PHI
3538
Stop cARt
Numberofindividuals
0
1000
2000
3000
4000
%ofPTC
70
French HIV data base (FHDH
ANRS CO4): www.ccde.fr
128117 patients (mean of follow
up: 7 years)
- 1 loss of
control at 6
years
- 1 PTC with
repeated low
level replication

6. OCP
0
1
2
3
4
5
TN TCM TTM TEM
0Day of Culture 3 6 8 10 13 0 3 6 8 10 13 0 3 6 8 10 13 0 3 6 8 10 13
CellcapacitytoproduceHIV
(LogHIV-RNA/HIV-DNAcopiesatD0)
PTC are infected with replication competent HIV-1
Saez-Cirion et al PLoS Path 2013
PRIMO
HIC
PRIMO
PTC
PRIMO
Non controllers
PlasmaRNAViralloadatPHI
(logcopies/ml)
0
2
4
6
8 p=0.002 p=0.68
PTC displayed high viremia
during primary infection
The virus can replicate in
CD4+ T cells from each
patient

7. The ANRS International VISCONTI
Post-Treatment Controller Cohort
20 PTC
Coordinators: A Saez-Cirion (HIPer, IP) & C Rouzioux (Necker)
7 new PTC, all early treated post-infection (Time off therapy: 6.5 years [2.8-14.0])
6 PTC from the ANRS iVISCONTI: 3 in the USA, 2 in Spain, 1 in Germany
1 teenager PTC: a paediatric case of durable remission

8. Durable cART free remission in a perinatally infected
teenager (French Pediatric Cohort ANRS EPF-CO10)
HIV-1 viral load and CD4+ T cell counts in the child.
Age (days)
0 500 1000 1500 2000
%CD4cells
0
10
20
30
40
50
Viralload(HIVRNAcopies/mlplasma)
101
102
103
104
105
106
107
ZDV
ZDV+DDI+3TC+RTV
DDI+3TC+RTV
DDI+D4T+RTV
DDI+D4T+RTV
Age (years)
6 8 10 12 14 16 18
%CD4cellsinblood
0
10
20
30
40
50
510
48
HIV-1 RNA:
<9 copies/ml of plasma 2013
<4 copies/ml of plasma 2014
<7 copies/ml of plasma 2015
HIV-1 DNA:
2.1-2.5 log copies/10^6 PBMC between 2013-2015
Low levels of replicating viruses detected in vitro
P. Frange et al. The Lancet HIV, 2015
ART 6 years
STOP

9. PHI
Chronic
cART
ALT
HIC
PTC
HIV-DNA(log10copies/106PBMC)
1
2
3
4
5
6
Saez-Cirion, Plos Path, 2013
Hocqueloux et al, JACS 2013
years under cART
HIVDNA(Log/MPBMC)
started in
primary infection
started in
chronic
infection
Treatment during primary HIV infection has a major impact
on the size of the viral reservoir
Hocqueloux et al, JAC 2013
A low viral reservoir is necessary but not sufficient for HIV remission..
What else ?
cART :
HIV reservoirs in PTC:
- - Mostly TTM subset
- - weak in TN and TCM subsets

10. France HIC
Allelefrequency(%)
0
10
20
30
40
50
60
B27
B57
B35
B07
Non favorable HLA and Weak CD8 T cell responses in PTC
Frange et al The Lancet HIV. 2015
PTC

11. Very weak HIV-specific CD8+ T cell responses detected in PTC
Saez-Cirion et al PLoS Path 2013
CD8+ T cells
PTC cART HIC
%ofCD127+onCD8+Tcells
30
40
50
60
70
80
90
CD8+ T cells
PTC cART HIC
%ofCCR7+onCD8+Tcells
0
10
20
30
40
50
60
CD4+ T cells
PTC cART HIC
%ofCD127+onCD4+Tcells
65
70
75
80
85
90
95
CD4+ T cells
PTC cART HIC
%ofCCR7+onCD4+Tcells
10
20
30
40
50
60
70
Samri et al IAS 2015
CD8 T cell response
PTC cART HIC
%ofCD
30
40
%ofCC
0
10
20
CD4+ T cells
PTC cART HIC
%ofCD127+onCD4+Tcells
65
70
75
80
85
90
95
%ofCCR7+onCD4+Tcells
10
20
30
40
50
60
70
CD4 T cell response

12. CD8+ T cells
PTC cART HIC
%ofCD38+onCD8+Tcells
5
10
15
20
25
30
CD8+ T cells
PTC cART HIC
%ofHLADR+onCD8+Tcells
0
10
20
30
40
50
60
CD8+ T cells
PTC cART HIC
%ofDR+CD38+onCD8+Tcells
0
2
4
6
8
10
12
14
16
18
PTC maintain control with low level of immune activation
HD VIR HIC PTC cART
CD69 NK cells
Scott-Algara et al CROI 2015
Saez-Cirion et al PLoS Path 2013
HD cART PHI PTC cART CHI HIC
IP-10(pg/ml)
101
102
103
104
p<0.05
p<0.05
Plasma IP-10
Monceaux et al Unpublished

13. PTC NK cells have with high anti-HIV activity
Scott-Algara et al CROI 2015
NK cells from PTC have better
capacity to control HIV infection
in autologous CD4 T cells
(measured by lower expression
of p24 and GFP)
HD VIR HIC PTC cART HD VIR HIC PTC cART
HD VIR PTCcARTHD PTCVIR cART
%ofrelativeinfection
(CD4vsNK:CD41:1)
%ofrelativeinfection
(CD4vsNK:CD41:1)
A peculiar subset of NK
cells involved in
controlling HIV in PTC?

14. PTC NK cells are phenotypically and functionally
different from EC NK
Open questions :
Are NK cells preserved to control HIV infection
in early treatment?? (Alter et al. 2015)
Is this NK phenotype and function related to
PTC genetic determinants ??
NK cell
IFN-γ
Cytokines ?
KIR2DL1
KIR2DL2
KIR3DL1
NKG2A
CD160 neg
NKp46 low
Low cytotoxic
Capacity?
Target cell
HLA ???
NK cells from PTC have a peculiar
phenotype:
- Higher expression of CD158a, CD158b and
NKG2A than EC and HD
- Lower expression of NKp46, CD160 and CD69
-High capacity to produce IFN-γ, but normal
degranulation (CD107a)
High capacity to control HIV?
Similarities with
non pathogenic
SIVagm infection
in AGM?

15. A
G
M
M
A
C
0
2 0
4 0
6 0
8 0
1 0 0
1 5 0 d a y s P .I
%ofIL-15follicles/LNsection
A G M
M A C
F
MAC
IL-15 in lymph node follicles
AGM
Higher NK cell activity in LN during SIVagm (non-pathogenic) compared
to SIVmac infection (pathogenic)
% of IL-15+ follicles
AGM
CD107+ NK
MAC
CD107+ NK
Perforin
IFN-g
CD107
AGM/SIV+ chronic phase
NK cells in AGM
LN follicles
Green: B cells
Yellow: NK cells
No SIV replication in
LN follicles

16. Macaque model of post-treatment control
Early vs delayed start of treatment
SIVmac / macaque
 Impact on viral reservoirs, inflammation and immune responses ?
Mechanisms responsible for remission ?
 Biomarkers predictive of control after treatment interruption ?

17. HIV Cure strategies:
Lessons from Long-term control in human and NHP
To limit the
establishment of the
reservoir
To reduce the size of
the reservoir

18. 2014-2016 Global Scientific Strategy
 Six themes and subgroups:
 Molecular Biology of HIV latency and shock strategies (Moncef
Benkirane & David Margolis)
 Viral reservoirs, immunology of HIV persistence and kill
strategies (Steven Deeks & Daniel Douek)
 Models for HIV cure or sustainable remission (Jintanat
Ananworanich & Jeffrey Lifson)
 Gene/Cell Therapy (Paula Canon & Daniel Kuritzkes)
 Novel Biomarkers and technologies to quantify/analyse HIV
reservoirs (Sharon Lewin & John Mellors)
 Social sciences and health system preparedness (Joseph Tucker &
Ying-Ru Lo)
 July 2016: Publication and Launch of the revised
Global Scientific Strategy at the AIDS 2016 in Durban.

19. Thanks you to…
And to all the patients, researchers and health
professionals who participate to HIV cure research…
JF. Delfraissy, O. Lambotte,
C. Rouzioux, L. Hocqueloux, P.
Frange...
M. Muller-Trutwin,
A.Saez-Cirion
D. Scott-Algara
And many others…
S. Deeks, S. Lewin and all the
members of the IAS HIV Cure
ISWG members
J. Whitescarver and all the
members of the IAS HIV Cure
Advisory Board
AL. Ross and R. Lamplough