titre du topo - european aids clinical society · resume therapy if cd4+ < 250 hiv disease...
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HIV
pathogenesis
Prof Christine Katlama
University Pierre et Marie Curie Paris VI
Pitié-Salpêtriere Hospital, Paris
Advanced
clinical course
Aix en Provence
August 2015
G.Braque
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HIV Pathogenesis
• HIV primary infection : a viro-immunologicaltsunami
• Establishement of HIV reservoirs
• HIV induced immune suppression
• HIV immune activation and inflammation
• Immune reconstitution
• HIV cure
HIV immune protection
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VIH: a smart predator prédateur unique
•Highly replicative virus : 10 billions
virions/ day silently for years
• Unique to target the master cell
of immune system
• A double profile : killing through
RNA and integrationg through DNA
• No effective immune protection
• No cure eradication
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Primary Infection : A defeated immune system in a viral tsunami
From A Haase et al. 2008
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HIV replicates
in lymphoïd tissues
where activation takes place
BAutran/14
Antigens
and
Cytokines
NF-kappa-B
gp120 gp41
protéaseRT
intégraseNF-AT
p17
MA
p24
CA
p7
NC
LTR viftatvpr
nefvpu
revtat
LTR
revpolSP-1
AP-1SP-1
AP-1
gag env
Voies de
signalisatio
n
CD3 / TCR
TCR/CD3MHC-II
+ Ag
Voies de
signalisatio
n
CD3 / TCR
HIV was discovered in lymphoïdtissues where the massive antigenstimulation of CD4 T cellsfavors HIV replication
HIV depends upon immune activation to replicate
F Barré-Sinoussi et
al.
Science,
May 1983,
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Early establishement of durable HIV
reservoirs
A Haase et al. 2008
Earlyestablishment of the HIV Reservoirsin CD4 cells
Immune responses to HIV:too little, too late
High level of infection in short-and long-lived CD4+ cells
Massive depletion of gut CD4
The OptiprimStudy:at Fiebig III(D30) post-infection
Bacchus&Cheret et al Plos One 2013
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Target cells for HIV
From Siciliano, AIDS 1999, 13 Suppl A : S49-58
Half-life (days)
0 3
0
6
0
9
0
12
0
?
Free Virions
Infected activated CD4 T cells
producing HIV
Resting CD4+ T cells harboring HIV DNA
Free Virions on follicular dendritic
cells (lymphoid tissues)
Infected Macrophages
(all tissues and sanctuaries)
NaiveCD4+cell
Apoptosis
Turnovereffectoreffector
TransitionalMemoryCD4 T
memorymemoryEffectorMemory
CD4 T
memorymemory
CentralMemoryCD4 cell
memorymemoryEffector
CD4 T
Heterogeneous CD4 T cells
with a wide range of
Half-lives and reproductive capacities
Various CD4+ target cells
TN TCM TTM TEM Effectors
Years Months Weeks Days
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JM. Brenchley, ..AT. Haase,and DC. Douek J Exp. Med. 2004
HIV-1 Infection is massively located in the Gastrointestinal Tract
with massive depletion of CD4 T Lymphocytes and durable
tissue alterations
S Mehandru,………P Racz, and M Markowitz, J Exp. Med. 2004
GI tract represents half the immune system
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Primary infection and HIV reservoir dynamics
• 68 patients starting ART within 2-3 days after contamination Avant tout traitement :
Total HIV DNA lower in Fiebig I
Unintegrated DNA not detected in détecté chez 22/24
(92 %) Fiebig I
Ananworanich J, CROI 2013, Abs. 47
p = 0,0007
p =0,01100 000
10 000
1 000
100
10
0
Fiebig I
(n = 24)
Fiebig II
(n = 7)
Fiebig III
(n = 36)
Total HIV DNA (c/106 PBMC) Integrated HIV DNA (c/106 PBMC)
100 000
10 000
1 000
100
10
0
Fiebig I
(n = 24)
Fiebig II
(n = 7)
Fiebig III
(n = 36)
p = 0,002
p = 0,0005
92 % 29 % 53 %Non détecté
Fiebig I: RNA+, p24̶ -, 3°G ELISA neg
Fiebig II: RNA+, p24+, 3G ELISA neg
Fiebig III: 3rd-gen ELISA+, WB neg
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Early establishement of durable HIV reservoirs
OPTIPRIM study in primary infection
The OptiprimStudy:at Fiebig III(D30) post-infection
Bacchus&Cheret et al Plos One 2013
High level of infection in
short-and long-lived CD4+ cells
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Early ART at primary infection massivelyreduces the size of HIV reservoir
Ananworanich J, et al. CROI 2013. Abstract 47.
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• Time of ART initiation appears to Be the KEY factor to mimimize HIV reservoir
Replicative viremia
HIV reservoir = cell associated HIV DNA
= HIV residual disease
• Early ART blocks the increase in HIV reservoir
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Evolution of HIV RNA and HIV DNA in patients following ART initiation
Ngo-Giang-Huong et al. AIDS. 15(6):665-673, April 13, 2001.
Primary
Chronic naive
Chronic experienced
Primary
Chronic naive
Chronic experienced
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HIV induced Immune suppression
ART leads to immune restoration
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Mechanisms of the CD4 lymphopenia
1- Destruction of CD4+ cells HIV-infected:
- Infection + replication HIV = cytopathogenicity (syncitia : X4)
- Destruction by anti-HIV immune responses
Non-infected:
- Apoptosis as a consequence of chronic activation
2- Defaults of cell regeneration
Central: Thymus : limiting production of naive CD4+ T cells
Peripheral : Anergy (loss of IL-2 production and proliferative
capacity): limiting central-memory T cells
Mean loss = 50 CD4/mm3/j 109 /j
1/2 life infected CD4 cells = 1,2 j (Perelson et al. 96)
BAutran
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MECHANISMS of CD4 LYMPHOPENIA
Progressive loss of Immune ressources
and memory to pathogens
• Rapid loss in naive CD4 cells
=> accelerated conversion towards memory cells
• Infection/Anergy of Memory CD4 T cells
cell destruction
Loss of Memory to Opportunistic infections
Thymus
(source) années
Ta
ux d
e C
D4
Naive CD4 cells(réservoir)
memory CD4 cells
4 8
BAutran
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Lymphocyte CD4 : the key driver of immune response
CD4
Fungi
parasites
bacteriaevirus
cancers
NK
CD8LB
PN
Mono/Mph
Guislaine Carcelain / Brigitte Autran
Antibodies
Cytokines
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Immune activation and HIV replication
Appay et al, J Pathol 08
HIV-1 infection and replicationmain target: CCR5+ activated CD4+ T-cells
Bacterialtranslocation
including TLR-ligands
Viralreactivation
in particular CMV
Anti-HIVImmune response
cellular and humoral
Production of HIV proteinsgp120, nef
Massive CD4+ T-cell depletionin particular mucosal CD4+ T-cells
Massive CD4+ T-cell depletionin particular mucosal CD4+ T-cells
Systemic immune activationAdaptive and Innate
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Pathogenesis of HIV
HIV
Immune activationInflammation
Immune deficit
Cardiovascular riskBone
Cognitive disordersCancers
Accelerated agingCancers
AIDS
Cancers
HBV/HCV
HIV is deleterious through a slow immune deficit ( AIDS) and a chronic inflammation/activation ( comomorbidities )
and immune activation
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ART leads to immune restoration
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Immune restoration following ART
1
10
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Months
Stim
ulat
ion
inde
x an
ti-CM
V
2
3
4
5
HIV
RNA
(log
copi
es/m
l)
CMV viremia
HIV viral load
CD4 counts
Stimulation index anti-CMV
Positive
CMV viremia
21
206
230
3) Restauration fonctionnelle des Ly CD4
0
5
10
15
20
0 2 4 6 8 10 12 14
% p
osi
tive
ce
lls
0,5
1
1,5
2
2,5
3
3,5
4
4,5
infe
ctiv
e c
ells
(lo
g10
)/1
07
PB
MC
CD4+DR+
CD4+45RO+DR+
CD3+8+DR+
HIV
months
2) Réduction de l’hyperactivation
…. Li TS et al. Lancet, 1998; AIDS Res. Retrov. 1999, .
1) Restoration of CD4 counts, naive & memory
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Long term CD4 cell reconstitution with ART
Garcia, J AIDS 2004
As ObservedAs Predicted
8 years4
600
200
1-22 - 3
7 - 10
> 10
2 4 6 8 10
6 - 8
4 - 5
HAART
B Autran et al. 1998
Some patients did not restore sufficiently their CD4 Nadir CD4 is a major unfavorable predictive factortowards death comorbidities and cancers
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HIV inducedactivation and inflammation
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Chronic Inflammation/activation plays a key role in
immunopathology of HIV:
Induction of Immune defects and Co-morbidities
Secretion of Pro-inflammatory
Cytokines
IL-1b, IL-6, TNF-a,….
Chimiokines
MCP-1, CX3CL1, RANTES,….
Inflammation-related Disorders
Atherosclerosis
Osteoporosis
Neurocognitive
Degeneration
= inflamm-ageing ?
Appay V et al, J Pathol 08
• Cellular Markers of Immune Hyperactivation : Ly CD4 and CD8 (Ki67,DR, CD38)
B (hypergammaglobulinemie, CD23s…)
Monocytes: CD14s, CD163s…
• Seric levels of Markers of Inflammation: pro-inflammatory Cytokines (IL-6, TNF, MCP-1, IP-10, IFN-alpha
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T-cell activation persists under ART despiteapparently optimal viral suppression
Hunt, JID 2008
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Inflammation ↑ Monocyte activation
↑ T cell activation
Dyslipidemia
Hypercoagulation
Microbial translocation
HIV-associated fat
Metabolic syndromeHIV production Excess pathogens
CMV HBV HCV
Loss of regulatory cells
Co-morbidities
Aging From S Deeks 2013
Persistence of Inflammation despite viral suppression
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Inflammation predicts disease in treated HIV infection,
as it does in the general population
• Mortality (Kuller, PLoS Med, 2008, Sandler JID 2011, Tien JAIDS 2011)
• Cardiovascular Disease (Baker, CROI 2013)
• Lymphoma (Breen, Cancer Epi Bio Prev, 2010)
• Venous Thromboembolism (Musselwhite, AIDS, 2011)
• Type II Diabetes (Brown, Diabetes Care, 2010)
• Cognitive Dysfunction (Burdo AIDS 2012)
• Frailty (Erlandson, JID 2013)
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2006 SMARTReplication of HIV is associated to an excess of morbi/mortality
0 4 8 12 16 20 24 28 32 36 40 44
VS
15
10
5
0
DC
p < 0,0001% c
um
ula
ted
eve
nts
Mois depuis la randomisation
El-Sadr W.,NEJM 2006,
SMART[4]
N = 5472
Randomized 1:1Continuous ART,
ART interrruption TI
CD4 > 350
Resume therapy if CD4+ < 250
HIV disease progression or death
TI associated with significantly greater disease progression or death, compared with CT: RR: 2.5 (95% CI: 1.8-3.6; P < .001)
AIDS or Deaths/100 pyTI 3.7VS 1.5
AIDS 93Death 79
Trial stopped
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SMART : Increase morbidity / mortality isassociated with imflamation and coagulation
markers
Marker Un-adjusted Adjusted
OR (4th/1st) P-Value OR (4th/1st) P-Value
Hs-CRP 2.0 0.05 2.8 0.03
Amyloid A 2.2 0.07 2.6 0.09
Amyloid P 0.7 0.39 1.1 0.84
IL-6 8.3 <0.0001 11.8 <0.0001
D-Dimer 12.4<0.0001 26.5 <0.0001
F1.2 1.0 0.92 1.2 0.66
*Adjusted for age, race, ART, VL, BMI, Cholesterol, Smoking, Hepatitis, Statins, BP med’s
Kuller LH, et al. PLoS Med. 2008;5:e203.doi;10.1371/journal.pmed.0050203
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START: when to start ART ?
Immediate ART GroupInitiate ART immediatelyfollowing randomization
N=2,326
Deferred ART GroupDefer ART until the CD4+ count declines
to <350 cells/mm3 or AIDS developsN=2,359
Primary composite endpoint, target = 213
Serious AIDS or death from AIDS
Serious Non-AIDS Events and death not attributable to AIDS CVD, ESRD, decompensated liver disease, & non-AIDS defining
cancers
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START Proportion of patients on ART with with HIV-RNA
≤200 copies/mL
% of Follow-up on ART
Immediate 94
Deferred 28
Deferred Arm: Median time to ART 3 years (IQR 1.6–4.8) (projected 4 years)
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START Types of Serious Events
AIDS eventsImm. ART
Def. ART
TB, pulm or extrapulm.*
6 20
Lymphoma, HL or NHL
3 10
Kaposi’s sarcoma 1 11
PCP 1 5
Herpes zoster, diss.
0 3
Other** 3 1
Any Serious AIDS 14 50
* Participants from Africa: 16/26 (62%) of TB cases** Cervical carcinoma, extra-pulm. cryptococcosis, CMV, recurrent bacterial pneumonia
Non-AIDS eventsImm. ART
Def. ART
Cancer, non-AIDS* 9 18
Cardiovascular disease* 12 14
Liver or renal disease 1 2
Death, other 7 13
Any Serious Non-AIDS
29 47
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Even Moderate Immune deficit increases risk of
non AIDS related cancers
HodgkinRR (95% CI)
Lung RR (95% CI)
LiverRR (95% CI)
Last CD4
>500
350-500
200-350
100-200
50 -100
<50
1,0
1,2 (0,7-2,2)
2,2 (1,3-3,8)
4,8 (2,8-8,3)
7,7 (3,9-15,2)
5,4 (2,4-12,1)
1,0
2,2 (1,3-3,6)
3,4 (2,1-5,5)
4,8 (2,8-8,0)
4,9 (2,3-10,2)
8,5 (4,3-16,7)
1,0
2,0 (0,9-4,5)
4,1 (2,0-8,2)
7,3 (3,5-15,3)
6,6 (2,4-17,6)
7,6 (2,7-20,8)
Guiguet et al Lancet Oncology 2012
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Early control of HIV replicationis the best way to preserve future
• Nadir of CD4 is a predictor for ART failure - death, comorbidities , cancer .
• High CD4 > 500/mm3 and normal CD4/CD8 ratio is the optimal way to preserve clinical future
• ART at primary infection :
– Suppresses immune activation
– Reservoir size limitation
• Optimize retention in care
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Is HIV cure
achievable ?
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Decrease reservoirFunctional cure : HIV remission
No plasma viral replicationRestored l immune function
No activation /inflammation
Eradicate reservoirSterilizing cure
Elimination of replication-competent virus
Suppressed plasma
viremia
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Obstacles to Eradication of the HIV Reservoirs
Residual Replication
Immune Activation
HIV LatencyHIV reservoir
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Spontaneouscontrol of HIV replication
Elite Controllers and LTNPsInfected for 10-30 years, No
ART Genetic Background;
Strong CD4 and CD8 response/HIV
Preserved CD4 TCM cells
Low immune activation
Post-TreatmentControllers (Visconti)
Control HIV without ARV for 3.5 y.
ARV for 5 years started at PHINo genetic backgroundLow Immune activation
Is HIV cure /remission achievable
French Hospital Data Base (FHDH): Grabar.. D Costagliola, AIDS 2009
On 46,880 HIV+ patients:
LTNP = 0.4%
Elite LTNP = 0.05%
HIV Controlers = 0.22%
Elite Controllers = 0.15%
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Elite Controlers as a model of Functional CureALT Cohort (ANRS CO-15)
Total (n=71)
CD4 count (/mm3) 639(489-751)
HIV-DNA (log cp106 PBMCs) 2.29(1.53-2.89)
plasma HIV-RNA (log cp/ml) 3.78 (2.57-4.56)
39
BL Characteristics
(r=0.81, p<0.0001)
12 ECs
ALT: 3-5 years follow-up (N =
48)
HIV-DNA
0
0,5
1
1,5
2
2,5
3
3,5
1 2 3 4 5 6 7 8 9 10
ECs : 5-10 y follow-up (N=10)
HIV DNA
pl-HIV RNA
Baseline Follow-up
Log c
opie
s
0,00
0,50
1,00
1,50
2,00
2,50
3,00
3,50
4,00
4,50
5,00
1 2 3 4 5
HIV
-DN
A l
og
co
pie
s/m
illio
n
PB
MC
s
Years
medianes
min
max
Correlation between HIV reservoirs and Virus production
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Post Treatment Controllers(PTC)Visconti Patients
No protective HLA profile
Low DNA
Low CD8 response
Reservoir less localized in
central memory cells
14 patients treated in primary infection
ART duration (med ) : 35 moisDuration off ART : 5 years
CD4 count - pre ART : 489 ( 371-955)- at stop : 931 (354-1639- last value : 837( 388-1598
HIV RNA - pre ART : 5.0 log ( 3 - 7.3)- last value : 1.7 log ( 1.7 -2.4)
After > 6 years without ART Median RNA = <20 copies/mLMedian DNA = 83 copies/M
PBMC
Saez Cirion et al Plos Path 2013
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SALTO ANRS 116Treatment interruption in patients treated at CD4 > 350 et VL < 50 000 cp/ml
95 patients
Age 40 years (IQR: 36–45)
Pre-cART values – CD4 : 454 /mL (392–576)
– VL : 4.3 log10 cp/ml (3.9 – 4.5)
– CD4 nadir : 382 /mL (340–492)
Duration of cART : 5.3 years (4.0–6.0)-
Baseline values – CD4 count : 813 cells/mL (695–
988),
– DNA : 206 copies/106 PBMCs
– (IQR : 53–556)
12 months post TI
7 /95 patients still had a VL<400 cp/ml
– KP: 7.5%, CI: 3.7-14.6)
4 kept a VL<400 copies/mL up to 36 months;
– All had CD4 cell >500/mm3
HIV DNA was the only significant predictorof maintaining VL < 400 cp/ml med value : < 10 vs 233 cp / 106PBMCs p < 0.001
Piketty et al, J Med Virol, 2010;82:1020-3 Assoumou et al, CROI 2013
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Immune Characteristicsin Models of Functional Cure
Lessons for therapeutic strategies towards a functional Cure of HIV ?
Early ART might control the HIV reservoirs in Visconti PTC
as efficiently as the « genetically-driven immune control of ECs
Frequency
GeneticTraits
Reservoiranddistribution
HIV specificImmunity
Immune activation
Transcriptionalprofiling
Elite Controlers
0.15-0.4% YES: MHC
Low
Low in TCM
StrongCD4, CD8 and Abs
Low Strong TCRLow IFN-alphasignatures
Post-TreatmentControlers
12-15%?No MHC
Low
Low in TCM
? Low ?
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Who controls viral replicationwithout ART ?
Elite controllers
Bone marrow transplant
Patients - baby or adults treated atprimary infection
Few chronic early treated patients
All these patients are characterized by
- Early ART or no ART
- low HIV DNA
- high CD4, High CD4/CD8
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ULTRASTOP: a pilot study
Can HIV remission off ARTwith HIV RNA < 400 cp/ML be
achieved in chronic patients with early start of ART :
– Total DNA < 100 cp/106 PBMC
– CD4 > 500/ mm3
– CD4/CD8 > 0.9
– Jamais de sida
– CV < 50 cp/mL for at least 2 years
A pilot study with 3 cohorts of 5 patients successively
enrolled if at least one success in the previous cohort
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ULTRASTOP: a pilot study
• Can HIV remission off ARTwith HIV RNA < 400
cp/ML be achieved in chronic patients with early
start of ART :
– Total DNA < 100 cp/106 PBMC
– CD4 > 500/ mm3
– CD4/CD8 > 0.9
– Jamais de sida
– CV < 50 cp/mL depuis 2 ans
• A pilot study with 3 cohorts of 5 patients
successively enrolled if at least one success in the
previous cohort
10 patients in 2 cohorts
DNA ultralow < 100 cp
CD4 > 500
5 years of viral suppression
One patient in remission ( 16 months)
9/10 rebounded within 4 weeks
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HIVReservoirs
ARV
Can we decrease the HIV
Reservoirs?
and stop ART?
Functional Cure ?
oreradicate HIV
Sterilizing Cure ?
Cure for HIV ? Is it achievable ?
CurrentModels of HIV Cure ?
LTNPsHIV/Elite Controlers
Post-TreatmentControlers
Berlin patient…
Mississipi baby
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Gene therapy
MaravirocAnti-inflammatory drugs- Statins- OH-Chlorochin
Potential strategies to reduce HIV reservoirs
Residual Replication
Immune Activation
HIV Reservoirs Latency
Massive CD4 T-cell depletionBacterial translocation
ARV Intervention
- Intensification- NevirapineSystemic Inflammation
Viral Co-Infections
Pre-Probiotics
Antiviral drugs
Anti-co-stimulatory molecules- anti PD1 / anti PDL1- anti-CTLA4
- anti-CD137
CD4DC
Quiescent T cells activation- IL7
Pre/post-transcriptional factors disruption
- HDACi- HMBA
Immune Intervention
- Anti-HIV vaccine
- IL7
Cellular Immunity
CD8
CD4
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Romidepsin : Impact on Plasma HIV-1 RNA
Viral load: COBAS® TaqMan® HIV-1 Test, v2.0TMA: Qualitative NAT screening system (PROCLEIX ULTRIO Plus, Genprobe)
No impact on DNA
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Why hav’nt we an HIV vaccine yet?
• A failure but not a lack of researches
• Obstacles against HIV vaccines : HIV escape
– Immediate and definitive HIV Integration in host genome
= Trojan Horse
– HIV Variability in Antibody and T cell epitopes (Enveloppe, Tat, Nef, Gag)
– Weak neutralizing antibodies
Difficulties are illustrated by
the lack of cure or spontaneous recovery from the HIV infection
BA ADVAC
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The search for an immune protection HIV vaccine:
T cell-based vaccines in Humans: The Prime-boost approach
Phase IIb studies of Recombinant Live vectors alone or combined to DNA
• AdenoVirus: Strong T cell immunogenicity but anti-vector pre-existing Abs
• Ad5-HIV-(Gag, Pol, Nef) clade B vaccines (no Env) (Merck)
=> 2005: A large Phase IIb trial in N &S americas, Australia, South-Afr.
= The STEP trial
• Pox-virus
• Canary-poxV (sanofi-pasteur): T cell immunogenicity in Humans but weak
=> 2004: A large Phase IIb trial with Clade B vaccines:
HIV-rec vCP(Env, Gag, Pol Nef) + gp120
= The Thaï Trial (with US gov.)
• Broad neutralizing antibodies
Time for Hope or for Despair?
BA ADVAC13
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The 2000s years :
The 2010s years :
Therapeutic vaccines against HIV : Changes in paradigms
Help CTL
HAART
+
vaccine
Autran et al NRI 2003, Science 2004, Exp.Rev.Vaccine2004, Immunol.Rev.2013
to limit : - time on therapy and
- disease progression when « off ART »
Murphy et al. Science 2009; Trono D. et al Nat.Med. 2010; the IAS Working Scientific group on HIV Cure, NRI 2012 Katlama C. et al.Lancet 2013Carcelain&Autran, Immunol. Rev. 2013
in synergy with anti-latency agents
to : - reduce or purge the HIV reservoirs
- allow functional cure of HIV
vCP : Tubiana (Vaccine 2005) (Autran 2008, Papagno 2009)
+ gp160: Markowitz( J Inf Dis, 2002)
+ Remune: Kinloch (J Inf Dis, 2002)
+ Lipopept.+IL2: Levy (Aids 2005, 06), Goujard (J Inf Dis 2007)
+/- IL2: M Kilby et al. (J Inf Dis, 2006)
Safety, Immunogenicity for CD4 T cells, CD8?
Modest impact on HIV or Enhancement !
Dendritic cells loaded in vitro :
+ Inactivated HIV: Garcia. (JID 2011, Science Trans.Med. 2013)
Transient reduction in Virus Load
D Richmann et al. Science 2009
Purging the HIV
reservoirs ?
• Anti-latencyagents
+ Vaccine CTLs/Abs
to kill residual cells producing HIV
to block cell to cell HIV spread
+
B Autran ADVAC
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HIV pathogenesis : key messages
HIV invades immune system within days withforever scars .
HIV reservoirs establishes very early HIV induces a massive activation /inflammation HIV is deleterious from early stages of disease CD4 nadir and CD4/CD8 are major prognostic
factor Activation/inflammation perists even in a context
of viral suppression Early , maximal and permanent viral control is the
best way to preserve future
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UPMC Clinical HIV unit :R Tubiana R.CalinMA Valantin F.Caby
L Schneider
Virology V . Calvez AG marcellin
Immunology : B. AutranG . Carcelain
Methodology D. Costagliola
ANRS INSERM UPMC ORVACS
From Edward Hopper