Can HIV be cured? (how about long term Drug free remission?)
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1 Can HIV be cured? (how about long term Drug free remission?) Shirin Heidari International AIDS Society EC Think Tank meeting October 2010 Luxemburg
2 HAART can control HIV, cannot eradicate it Life long treatment Cost Adverse effect Risk for CVD and cancer with age High Active Antiretroviral Therapy (HAART) Adherence Transmission Resistance
3 Growing need Estimated number of people in need of ART 14,6 million (from 10,1 million ) For each person put on HAART = 2-3 person newly infected Therapeutic cure and prophylactic vaccines are rational ways to tackle the epidemic. Source: Towards Universal Access, Progress Report September 2010
4 1996/1997 >3 years of HAART to eradicate HIV?
5 Courtesy of Nicholas Chomont
6 Ongoing viral replication occurs in subjects on suppressive HAART (TW Chun, JCI ; N Tobin, J Virol 2005). HIV integrate in long lived resting memory T cells and persist despite suppressive HAART(TW Chun, Nat. Med 1995, D Finzi, Science ; TW Chun, PNAS 1997). Reservoir cells, like other memory T cells, divide very slowly to maintain the memory of the immune system (A. Bosque and V. Planelles) Courtesy Courtesy of of Nicholas Nicholas Chomont Chomont
7 The Berlin Patient 2007/2008 Gero Hutter
8 HIV patient functionally cured by bone marrow transplant Proof Of Concept Healthy donor with CCR5 mutation Stem cells without CCR5 HIV positive recipient
9 Objectives: Present state of the art research on the control of HIV reservoirs Accelerate research towards a potential HIV cure Highlight the importance of basic science to the HIV response Re-engage the broader HIV community in basic science Strategize to accelerate the translation of findings into clinical practice Provide a networking opportunity for HIV scientists to share ideas and debate with peers
10 2010 IAS Workshop Towards a Cure: HIV Reservoirs and strategies to control them 199 attendees 65 Scholarship recipients 62 abstracts presented 9 invited speakers Clinical Implications of HIV Persistence HIV Reservoirs and Sanctuary Sites HIV Reservoirs and Mucosal Immune Restoration during HAART Mechanisms of Persistence in HIV Infected Individuals The role of the immune system in HIV persistence The role of host factors in HIV persistence Potential therapeutic interventions and how to evaluate them Eradication versus remission: is eradication possible? IAS/ANRS Young Investigator Award on HIV Reservoirs Review in Science: HIV Persistence and the Prospect of Long-Term Drug-Free Remissions for HIV-Infected Individuals (Trono et al.) Abstract and meeting report Supplement in Journal of the International AIDS Society
11 IAS workshop Towards a Cure AIDS2010 Vienna Brief Overview of ongoing research on HIV reservoirs and mechanisms of persistence
12 Eradicating cure Elimination of all HIVinfected cells HIV RNA < 1 copy/ml Cure Functional cure Long term viral suppression in absence of HAART HIV RNA < 50 copies/ml Remission Inspired by Sharon Lewin, AIDS 2010 Plenary «Strategies for a Cure»
13 How to control /reduce HIV reservoirs? Intensification of HAART (+/- other interventions) Early initiation of HAART (limit viral reservoirs) Improved Drugs (penetrating anatomical compartments) Treatment intensification does not reduce residual HIV-1 viremia in patients on HAART (Dinoso et al PNAS 2009) HIV-1 replication and immune dynamics are affected by Raltegravir intensification of HAART-suppressed subjects (Buzon et al Nat Med 2010) HAART intensification (plus raltegravir and maraviroc) in combination with other interventions (HIV vaccine (DNA+rAd5 or Immunomodulator IL7): Eramune 1& 2 (Katlama/Autran) HAART initiation during acute infection limit the frequency of latently infected cells and preserve HIV specific memory CD4 T cells (Trono et al, Science 2010, Chun et al PNAS 2001) A high HIV DNA level in PBMCs at antiretroviral treatment interruption predicts a shorter time to treatment resumption, independently of the CD4 nadir (Pikett et al J Med Virol (ANRS 116 SALTO Study Group))
14 How to control /reduce HIV reservoirs? Reactivation of HIV replication from latent reservoirs: Shock and Kill Courtesy of Nicholas Chomont IL-7 reactivates latent HIV in vitro, also improves HIV-specific immune response but also promotes homeostatic proliferation of HIV latently infected cells (Trono et al, Science) HDAC inhibitors & chromatin modifiers: may reactivate HIV production thereby reducing the pool of latently infected cells (Torno et al, Science) Gar1041 (an experimental leukemia drug) in combination with HAART transiently reduces the proviral DNA reservoir in SIVmac251-infected macaques, (Savarino, Abstract; the IAS HIV Reservoirs Workshop 2010) First encouraging results (Italy) in laboratory and primate model for potential long term remission Purging the Reservoir by Disrupting the PD-1 negative pathway during HAART? (Da Fonseca, Abstract: the IAS HIV Reservoirs Workshop 2010)
15 How to control /reduce HIV reservoirs? Interfering with immunological mechanism that contribute to HIV persistence Other therapeutic interventions (Gene/Mol therapy, ther. vaccine) Courtesy of Nicholas Chomont Reservoir are maintained by Immune regulators such as PD-1 and Ki67 (Da Fonseca, Abstract: the IAS HIV Reservoirs Workshop 2010, Chomont Nat Med 2009) Eramune 02 Therapeutic Vaccine + Integrase Inhibitor + anti-ccr5 (Clinical Trial NCT ) A model for an immune control of the HIV Reservoirs in HLA-B27/57+ LTNPs, (Descours et al, submitted) Targeting pathways downstream of homeostatic proliferation (Chomont et al. Nat Med 2009). Zinc-finger nucleases to disrupt CCR5 in progenitor stem cells - control of HIV in mice (Holt & Cannon: Nature Biotechnology 2010)
16 While we are searching for a cure: Keep patients ready by: Universal Access Early Treatment (Limiting the reservoirs and preserve immune system) Invest in research: Better understanding of biological mechanism and role of the immune system in establishing reservoirs and persistence Better tools and models In vitro and in vivo models More precise assays and sensitive techniques Drug development: increased specificity for latently infected cells Translational Research Inspired from Sharon Lewin, AIDS 2010 Plenary «Strategies for a Cure»
17 Global Scientific Strategy Towards an HIV Cure IAS to coordinate and support the creation of an international multidisciplinary scientific advisory group on HIV Reservoirs to develop a Global Scientific Strategy «Towards an HIV Cure» A Global Scientific Consortium «Towards an (functional) HIV Cure»?
18 The strategic role of the EU Global Scientific Strategy «Towards a (functional) HIV Cure»? Invest in research on HIV reservoirs Include a specific call in FP7 (Coordinated Action?) International HIV Reservoir Research Consortium?
19 Acknowledgements International AIDS Society, Geneva Marie-Capucine Penicaud Tamara Torri Anthony Flynn With courtesy of members of IAS programme committee Towards An HIV Cure who shared their slides: Françoise Barré-Sinousi, Institute Pasteur, Paris, France Nicolas Chomont, Vaccine and Gene Therapy Institute Florida, USA Tae-Wook Chun, National Institutes of Health, USA Alain Lafeuillade, Department of Infectious Diseases, General Hospital, Toulon, France Sharon Lewin, Burnet Institute, Melbourne, Australia
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