Overview of scientific advances toward an HIV cure Sharon R Lewin Director, Infectious Disease Unit, Alfred Hospital Professor, Department of Medicine, Monash University Co-head, Centre for Virology, Burnet Institute, Melbourne, Australia 13th European AIDS Conference, Belgrade, Oct 2011 Outline Why can’t cART cure HIV? What are potential strategies to achieve a cure? Current clinical trials aimed at cure Current and future challenges why can’t cART cure HIV? Rapid rebound in virus when cART stopped HIV RNA CD4 count 50 0 1 Years on HAART off cART HIV DNA CD4 count HIV RNA HIV DNA in infected cells is always detectable 50 0 1 Years on cART Chun et al., Nature 1997; 387:183; Finzi et al., Science 1997; 278:1295; Wong et al., Science 1997; 278:1291 HIV DNA CD4 count HIV RNA No such thing as an “undetectable viral load” 50 1 0 1 Years on cART Palmer et al., Proc Natl Acad Sci U S A. 2008;105:3879-84 Maldarelli et al., Plos Pathogens 2007; 3:484 Barriers to cure Latently infected T-cells Residual viral replication Anatomical reservoirs HIV latency and infection of resting T-cells cART Activated CD4+ T-cell Resting CD4+ T-cell Tissue chemokines Eckstein et al, Immunity 2001; 15: 671; Kreisberg et al., J Exp Med 2006; 203:865; Saleh et al., Blood 2007; 110:416; Marini et al., J Immunol 2008; 181: 7713-20; Bosque and Planelle, Blood 2009; 113:58; Cameron et al., Proc Natl Acad Sci 2010; 107(39):16934 Latently infected T-cells cART Latent infection can be established in many T cells Bone marrow Thymus Peripheral circulation Ag M M M M Naive Multipotent progenitor cells Naïve T cells Effector/ transitional Transitional memory Central memory Central memory Latent reservoir Chun et al., Nature 1997; 387:183; Finzi et al., Science 1997; 278:1295; Brooks et al., Nat Med 2001; 7:459 ; Chomont et al., Nat Med 2009; 15: 893; Dai et al., J Virol 2009: 83(9):4528-37; Carter et al., Nat Med 2010; 16: 446; Wightman et al., J Infect Dis 2010; 202(11):1738-48; Carter et al., Cell Host Microbe. 2011;9(3):223-34. Residual replication cART cART Immune activation associated with viral persistence in tissue Hatano et al., 6th IAS Conference, Rome, 2011 Anatomical reservoirs Anatomical reservoirs DCs, macrophages, astrocytes cART cART GI tract is a significant viral reservoir on cART HIV DNA per million cells HIV DNA N=8, time on cART with undetectable HIV RNA 2.8 – 12 years Chun et al., J Infect Dis 2008; 197:714; Yukl et al., J Infect Dis 2010 202:1553 What are potential strategies to achieve a cure? Cure or remission? Cure Remission Infectious Diseases model Elimination of all HIVinfected cells HIV RNA < 1 copy/ml Cancer model Sterilising cure Long term health in absence of HAART HIV RNA < 50 copies/ml Functional cure Strategies for cure Eliminate residual virus replication Eliminate latently infected cells Make cells “resistant” to HIV Enhance HIV-specific immunity current clinical trials aimed at cure Eliminating viral replication: treatment intensification HIV RNA HIV DNA CD4 count T20 LPV/r ATV/r Raltegravir (x4) Maraviroc (x2) 50 1 0 1 Years on HAART intensification Dinoso et al., Proc Natl Acad Sci U S A, 2009. 106(23): 9403-8; McMahon et al., Clin Infect Dis, 2010. 50(6): 912-9; Ghandi et al., J Infect Dis. 2010.201(2):293-6 and CROI 2011 ; Buzon et al., Nat Med, 2010 16: 460; Ghandi et al., Plos Med 2011; Yukl et al., AIDS 2010; Hatano et al., J Infect Dis 2011; Hunt et al., CROI 2010 Cell-to-cell infection not blocked by cART Cell free infection Cell-cell infection e.g., lymphoid tissue cART + • Reduce immune activation • Inhibit cellular not viral targets • Enhance tissue penetration of cART Sigal et al., Nature, 2011; 477(7362):95-8 Eliminate latently infected T-cells: activate latent HIV cART Activated CD4+ T-cell Resting CD4+ T-cell Activating latent HIV The Economist, July 17, 2011 Licensed drugs that activate latently infected cells Phase Phase Phase I II III Histone deacetylase inhibitors Methylation inhibitor Cytokine Anti-alcoholic Vorinostat Romidepsin Panabinostat Entinostat Belinostat Givinostat Others (9) Licensed Yes Yes # Latency Trials* trials 176 32 94 20 28 7 2 5-azacytidine >26 Interleukin-7 52 1 20 1 Disulfiram Yes * Total number of trials listed on http://clinicaltrials.gov (July 2011) Prince et al. Clin Canc Res 2009;15:3958; Contreras et al, J Biol Chem 2009; 284: 6782; Archin et al AIDS Res Hum Retroviruses 2009;25:207; Xing et al., J Virol; 2011;85(12):6060-4; Friedman et al., J Virol. 2011;85(17): 9078-89; Matalon et al., Mol Med. 2011 May-Jun;17(5-6):466-72 Saleh et al., Retrovirology 2011 (in press) Virus released from latency (% maximal stimulation) Combination therapy: enhances potency of activation HDACi 100 + 80 60 40 20 0 ND IL -7 tin tin α a a r F t tr s s N o o T pr pr + -7 IL Saleh et al., Retrovirology 2011 (in press) Prostratin or Bryostatin or methylation inhibitor Reuse et al., Plos One 2009; 4:e6093; Burnett et al., J Virol. 2010 Jun;84(12):5958-74 Perez et al., Curr HIV Res. 2010 Sep 1;8(6):418-29; Van Lint, 6th IAS, Rome 2011 HDACi turn HIV genes “on” HDACi OFF TF Bolden et al., Nat Rev Drug Disc 2006;5:769; Prince et al. Clin Canc Res 2009;15:3958; Contreras et al, J Biol Chem 2009; 284: 6782; Archin et al AIDS Res Hum Retroviruses 2009;25:207; Wightman et al., Immunol Cell Biol 2011(in press) Vorinostat (SAHA) Potent HDAC inhibitor Activates HIV from latency in vitro Licensed for cutaneous T cell lymphoma Multiple phase II trials for other malignancies including lymphoma, myeloma, solid tumors Oral administration Long term toxicities unknown Contreras et al, J Biol Chem 2009; 284: 6782; Archin et al AIDS Res Hum Retroviruses 2009;25:207; Saleh et al., Retrovirology 2011 (in press); Wightman et al Immunol Cell Biology 2011 (in press) Will HDACi turn HIV genes on in vivo? n=20 0,2,8 hours * Rectal biopsy Suppressive cART > 3 years Vorinostat 400 mg/day screen 0 2 7 * Primary endpoint 14 * Cell associated HIV RNA 21 28 and 84 Latently infected cells are rare Make cells “resistant” to HIV: gene therapy cART Activated CD4+ T-cell Silence or eliminate HIV Gene therapy Reduce CCR5 Resting CD4+ T-cell Amado et al., Hum Gene Ther 2004: 15:251-62; An et al., PNAS 2007: 104:13110-5; Digiusto et al., Science Transl Med 2010; 2:36; Holt et al., Nature Biotechnol 2010;28(8):839-47; Lalezari et al., 18th CROI, Boston, Feb 2011 abstract 46; Tebas et al., 18th CROI, Boston, Feb 2011 abstract 165 Nucleases chop up DNA: eliminate CCR5 expression or eliminate HIV CCR5 Naldini et al., Nature Genetics 2011; 12:301; Holt et al., Nature Biotechnol 2010;28(8):839-47; Lalezari et al., 18th CROI, Boston, Feb 2011; Aubert et al., PLoS One. 2011 Feb 9;6(2):e16825 Gene therapy to eliminate CCR5: Sangamo Biosciences Inc, SB728-902 SB728-902 SB728-T n=6 Aviremic patients on cART CD4>450 Treatment interruption Lalezari et al., 18th CROI, Boston, Feb 2011 Ando et al., ICAAC, Chicago, Sept 2011 Gene therapy to eliminate CCR5: SB728T % bi-allelic CCR5 modified cells correlated with viral suppression Ando et al., ICAAC, Chicago, Sept 2011 current and future challenges for HIV cure Scientific challenges Multiple barriers to eradication meaning a combination approach will be likely Better in vitro and animal models to evaluate new strategies, alone and in combination Drug development to increase potency and specificity for activating latently infected cells and/or enhanced tissue delivery Role of immune activation: driver of residual replication or a consequence of virus persistence? Clinical and implementation challenges Universal access to cART must remain a top priority PLWHA on cART are doing well so any intervention must have limited or no toxicity Clinical endpoints for successful “eradication” unclear. When will a treatment interruption be OK? Multiple unknowns with gene therapy: safety of delivery vectors, DNA nucleases and long term impact of CCR5 suppression We need a cure that is scalable, deliverable and cheap http://www.afripol.org/africa-newspapers/3-africa/2-newshour-with-jim-lehrer-africa-coverage-pbs.html Funding for research toward a cure for HIV Developing a road map for cure www.iasociety.org The Rome Statement Acknowledgements Department of Medicine, Monash University – – – – – – – – – – – – Paul Cameron Suha Saleh Miranda Xhilaga Candida Da Fonseca Pereira Ajantha Solomon Georgina Sallman Fiona Wightman Vanessa Evans Sam Ramanayake Melissa Chow Paula Ellenberg Miranda Xhilaga The Alfred Hospital – – – – Julian Elliott Jennifer Hoy Janine Roney Gregor Brown ACBD, Monash University – Anthony Dear Burnet Institute – – Anthony Jaworwski Melissa Churchill Peter Macallum Cancer Institute – Miles Prince National Association of People living With AIDS – – Jo Watson Bill Whittaker Merck – – Charles Farthing Daria Hazuda
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