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Washington D.C., USA, 22-27 July 2012www.aids2012.org Viral Eradication: The Cure Agenda AIDS Research Institute (IrsiCaixa) Autonomous University of Barcelona.

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Presentation on theme: "Washington D.C., USA, 22-27 July 2012www.aids2012.org Viral Eradication: The Cure Agenda AIDS Research Institute (IrsiCaixa) Autonomous University of Barcelona."— Presentation transcript:

1 Washington D.C., USA, 22-27 July 2012www.aids2012.org Viral Eradication: The Cure Agenda AIDS Research Institute (IrsiCaixa) Autonomous University of Barcelona (UAB) Catalan Institution for Research and Advanced Studies (ICREA) Javier Martinez-Picado

2 Washington D.C., USA, 22-27 July 2012www.aids2012.org Outline  Limitations to cure HIV  Potential strategies to achieve a cure  Current clinical trials aimed at cure  Towards an HIV cure pipeline

3 Washington D.C., USA, 22-27 July 2012www.aids2012.org HIV RNA (cps/mL) 50 Years on cART 0 1 1 Chun, Nature 1997; Chun, J Infect Dis 1997; Lewin, J Virol 1999; Palmer, PNAS 2008; Yukl J Infect Dis 2010 Cell associated HIV RNA Plasma single copy assay Cell associated HIV DNA Infectious virus (IUPM) Blood Tissue Cell associated HIV DNA Cell associated HIV RNA After 25-years improving therapies HIV cure is not feasible yet

4 Washington D.C., USA, 22-27 July 2012www.aids2012.org Why do we need to cure HIV?  Life expectancy remains reduced on cART  Ongoing morbidity on cART  Prevent HIV transmission  Substantial stigma and discrimination  Lifelong cART:  adherence  toxicity  long term-cost Lohse, Ann Int Med 2007; Hogg. Lancet 2008; Deeks & Phillips, BMJ 2009; May, BMJ 2011 Estimated 2015 AIDS investment for universal prevention, treatment, care and support 22 billion USD

5 Washington D.C., USA, 22-27 July 2012www.aids2012.org Barriers to cure HIV infection Where is the virus and how is it maintained in the face of suppressive therapy? Residual replication Latent infection inflammation immune activation

6 Washington D.C., USA, 22-27 July 2012www.aids2012.org Residual viral replication Hermankova, JAMA 2001; Persaud, J Virol 2004; Sedgahat, PLoS Pathog 2007; Chun, J Infect Dis 2008; Buzon. Nat Med 2010; Brennan, J Virol 2009; Dinoso, PNAS 2009; Yulk, J Infect Dis 2010;Yulk, AIDS 2010; Sigal, Nature 2011; Llibre, Antiv Ther 2012; Fletcher. CROI’12; Joseffson. CROI’12 Differential drug penetration in tissues Biological markers  Sensitivity  Interpretation Stable RNA or DNA following cART intens ART intensification RNA or DNA Greater HIV burden in tissues www.neurosolutionsnow.net No genetic evolution (absence of DRM) <50 c/mL Cell-to-cell transmission

7 Washington D.C., USA, 22-27 July 2012www.aids2012.org How latency is established and maintained in T-cells Eckstein, Immunity 2001; Swiggard, J Virol 2005; Saleh, Blood 2007; Marini, J Immunol 2008; Bosque, Blood 2009; Cameron, PNAS 2010; Lassen, PLoS One 2012 Activated CD4+ T cell Resting CD4+ T cell cART Negative regulators Survival (long-half life) Homeostatic proliferation

8 Washington D.C., USA, 22-27 July 2012www.aids2012.org Potential strategies to achieve a cure

9 Washington D.C., USA, 22-27 July 2012www.aids2012.org HIV cure: 2-models

10 Washington D.C., USA, 22-27 July 2012www.aids2012.org Strategies to cure HIV Treatment optimization & intensification (eliminate all replication) Reversal of HIV latency (increase viral production) Immune-based therapies (reverse pro-latency signaling) Therapeutic vaccination (to enhance host-control) Gene therapy

11 Washington D.C., USA, 22-27 July 2012www.aids2012.org Clinical trials: treatment intensification

12 Washington D.C., USA, 22-27 July 2012www.aids2012.org Treatment intensification studies in patients successfully treated with HAART StudynWeeks CD4 T-cells SCA Cell-associated DNA or RNA Immune activation Buzon et al. Nat Med ‘10 Llibre et al. Antiv Ther ‘12 69 48 RAL >500No Yes: 2LTRs No: total/integrated HIV DNA Yes: %CD38 + of CD8 + RO + Gandhi et al. PLoS Med ‘10 49 12 (+12) RAL >500No– Hatano et al. JID ‘11 30 24 RAL <350 No– MacMahon et al CID ‘10 10 4 RAL 474No–– Dinoso et al. PNAS ‘09 9 12 EFV,LPVr,ATVr 564No–– Yulk et al. AIDS ‘10 7 12 RAL 473 No Yes: unspliced RNA/10 6 CD4 + T cells in the ileum No: total HIV DNA Trend + Gut

13 Washington D.C., USA, 22-27 July 2012www.aids2012.org Current clinical trials: activating latency

14 Washington D.C., USA, 22-27 July 2012www.aids2012.org Activating latent HIV: in vitro Cytokines IL-7 1,2 IL-15 3 IFNa 2b Histone deacetylase (HDAC) inhibitors 4,5 Anti-alcohol agent Disulfiram 6 Methylation inhibitors 5-aza-dC 7 Immune modulation Anti PD1 NF-kB activators Prostratin, PMA, TNF  4 Akt/HEXIM-1 modulators HMBA 8 Histone Methyltransferase inhibitors (HMTI) 9 Chaetocin, BIX-01294 Other Quinolines 10 Combination enhances potency 4,9,11 1 Wang, J Clin Invest 2005; 2 Saleh, Retrovirol 2011; 3 Chomont, 6 th IAS Rome 2011; 4 Contreras, J Biol Chem 2009; 5 Wightman, Immunol Cell Biol 2012; 6 Xing, J Virol 2011; 7 Friedman, J Virol 2011; 8 Contreras PLoS Pathog 2007; 9 Bouchat, AIDS 2012; 10 Xing, J Antimicrob Chemother 2012; 11 Reuse, PLoS One 2009

15 Washington D.C., USA, 22-27 July 2012www.aids2012.org ERAMUNE: treatment intensification, activation and enhance immunity Primary endpoint – HIV DNA in PBMC DNA prime Arm A Arm B HIV rAd5 ERAMUNE 02 US/Canada n=28 828560week32 IL-7 Arm A Arm B ERAMUNE 01 EUROPE cART + (Raltegravir + Maraviroc) n=29 NCT01019551 & NCT00976404 cART + (Raltegravir + Maraviroc) Gag,Pol,Nef,Env Clades A,B,C Gag-Pol, Env Clades A,B,C

16 Washington D.C., USA, 22-27 July 2012www.aids2012.org Interferon-alpha intensification in individuals on ART NCT01295515  No effect on plasma viremia or total cell-associated HIV DNA  Reversible increase in immune activation (CD8 + CD38 + ) cells  IFN alpha approved to treat hepatitis C infection  Reduces the level of HIV in non-treated individuals 0448–4week IFNa-2bPre-IFNPost-IFN  n=4; NIAID/CCMD Clinic, Univ of Pittsburgh  cART>1 year; HIV RNA 0.6; CD4>300 cells/µl

17 Washington D.C., USA, 22-27 July 2012www.aids2012.org HDACi turn HIV genes “on” TF OFF Bolden, Nat Rev Drug Disc 2006; Prince. Clin Canc Res 2009; Contreras, J Biol Chem 2009; Archin AIDS Res Hum Retrovir 2009; Reuse, PLoS One 2009; Burnett, J Virol 2010 HDACi DNA nucleosomes

18 Washington D.C., USA, 22-27 July 2012www.aids2012.org  Potent HDACi licensed for cutaneous T-cell lymphoma  Endpoint is US viral RNA:  in resting CD4 + T cells  in total CD4 + T cells in blood & rectum NCT01365065 & NCT01319383 Vorinostat (SAHA) * * cART Vorinostat 400 mg/day 071421841 rectal biopsies day 28 3 AUSTRALIA n=20 leukapharesis * cART 200mg400mg 243 * visit * 15 PK USA n=8 400mg  Stable cART >6 months; HIV RNA 300 cells/µl

19 Washington D.C., USA, 22-27 July 2012www.aids2012.org Up to 48 x 1 million resting cells assayed Mean 4.8-fold induction (range 1.5- to 10-fold) All increases significant (p<0.01) No AE due to VOR Archin et al. CROI 2012; Full cohort (n=8) Archin et al. Nature in press Vorinostat induces HIV transcription in vivo

20 Washington D.C., USA, 22-27 July 2012www.aids2012.org Disulfiram Xing. JVirol 2011; NCT01286259; Spivak, 19 th CROI, Seattle 2012, #369  FDA approved drug to treat alcoholism  Reactivates HIV gene expression in an in vitro model of latency  Transient increase of low-level viremia after the 1 st dose  No decrease of the latent reservoir (IUPM) cART Disulfiram 500 mg/day 0714843 Day 10 IUPM  n=14; JHH & UCSF  cART>18 months; HIV RNA 200 cells/ µ l

21 Washington D.C., USA, 22-27 July 2012www.aids2012.org Current clinical trials: making cells resistant to HIV

22 Washington D.C., USA, 22-27 July 2012www.aids2012.org scBMT (X2) Donor Hütter. NEJM. 2009; Allers. Blood. 2010 HIV-1+ AML CCR5+ CCR5– HIV-1– ? CCR5– off ART no viral rebound Long-term control of HIV by CCR5 Δ32/Δ32 stem cell transplantation Chemotherapy (x4) Total-body irradiation (x2)

23 Washington D.C., USA, 22-27 July 2012www.aids2012.org Nucleases chop up DNA: eliminate CCR5 expression or eliminate HIV Holt, Nat Biotechnol 2010; Naldini, Nat Gen 2011; Lalezari, CROI’11 CCR5 Gene disruption

24 Washington D.C., USA, 22-27 July 2012www.aids2012.org Gene therapy to eliminate CCR5 NCT01252641 & NCT00842634; Lalezari, CROI’11  CCR5-disrupted T cells engraft, proliferate, and persist in peripheral blood and rectal mucosa  Increase CD4 T-cell counts and normalization of CD4:CD8 ratio after single infusion  The treatment is well tolerated SB728-902

25 Washington D.C., USA, 22-27 July 2012www.aids2012.org What else … ?

26 Washington D.C., USA, 22-27 July 2012www.aids2012.org The Global Scientific Strategy “Towards an HIV Cure” was launched on 19 July 2012! “Towards an HIV Cure” www.iasociety.org

27 Washington D.C., USA, 22-27 July 2012www.aids2012.org Int’l scientific collaborations Interaction between Basic + Clinical Science Interaction between Basic + Clinical Science Data exchange platforms between pilot studies New concepts, new generation New concepts, new generation Cross-talk with other scientific disciplines Cooperation public + privates sectors Cooperation public + privates sectors Community engagement Funding An Integrated Strategy

28 Washington D.C., USA, 22-27 July 2012www.aids2012.org Stakeholders’ Advisory Board

29 Washington D.C., USA, 22-27 July 2012www.aids2012.org 1. Review basic science to understand the cellular, viral and immunological mechanisms that control HIV persistence 2. Develop new assays and experimental models to tackle viral reservoirs (tissues and cellular sources) in long term ART-treated individuals 3. Investigate new therapeutic agents and immunological strategies to achieve viral remission in absence of cART Scientific and technical challenges ahead

30 Washington D.C., USA, 22-27 July 2012www.aids2012.org  Community engagement  Expectations, acceptability of cure strategies  Ethical & Regulatory issues  Risks and toxicities  Cost-effectiveness  Safe, affordable and scalable cure strategies  Ensure its availability to all patients wherever they live  Cure & Vaccine research are two inseparable priorities towards a world free of AIDS Other critical considerations

31 Washington D.C., USA, 22-27 July 2012www.aids2012.org Acknowledgements Sharon Lewin (Monash University, Melbourne, Australia) Steve Deeks (Univ. California San Francisco, USA) Françoise Barré-Sinoussi (Institut Pasteur, Paris, France) Ventura Clotet and colleagues (IrsiCaixa, Badalona, Spain) Christine Katlama (Univ Pierre et Marie Curie & Orvacs, Paris, France) Frank Maldarelli (NCI, Bethesda, USA) David Margolis (Univ North Carolina-Chapel Hill, NC, USA) Pablo Tebas (Univ. of Pennsylvania, USA) IAS “Towards the HIV cure” Working Group Marie-Capucine Penicaud Rosanne Lamplough

32 Washington D.C., USA, 22-27 July 2012www.aids2012.org … its complexity should not prevent the attempt HIV-1 cure research … … meanwhile, continuous investment to secure universal access to prevention, treatment, care and support must remain a TOP PRIORITY

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