1 / 40

Outline

hua
Download Presentation

Outline

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Cure research overviewSharon R LewinDirector, Infectious Disease Unit, Alfred HospitalProfessor, Department of Medicine, Monash UniversityCo-head, Centre for Virology, Burnet Institute, Melbourne, AustraliaCommunity Scientific Literacy Workshop “Towards an HIV Cure”, July 22nd., 2012, Washington DC

  2. Outline • What are the major barriers to cure? • Measuring virus persistence in patients on cART • What are potential strategies to achieve a cure • Current clinical trials for HIV cure

  3. what are the major barriers to cure?

  4. Rapid rebound in virus when cART stopped CD4 count HIV RNA 50 0 1 Years on cART off cART

  5. Barriers to cure • Latently infected T-cells • Residual viral replication • Anatomical reservoirs

  6. cART Resting CD4+ T-cell 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 HIV latency and infection of resting T-cells Activated CD4+ T-cell Tissue chemokines

  7. cART Latently infected T-cells

  8. cART cART Residual replication

  9. Anatomical reservoirs

  10. Variable penetration of ARV in tissue Fletcher, 19th CROI, Seattle 2012

  11. measuring virus persistence in patients on cART

  12. Virus persists in all patients on cART Tissue Cell associated HIV DNA Cell associated HIV RNA Cell associated HIV DNA Cell associated HIV RNA Infectious virus (IUPM) Plasma single copy assay 1 Blood HIV RNA 50 0 1 Years on cART Chun et al., Nature 1997; 387: 183; Lewin et al., J Virol 1999; 73:6099; Palmer et al., Proc Natl Acad Sci U S A. 2008;105:3879; Chun et al., J Infect Dis 1997;195:1762; Yukl J Infect Dis 2010;

  13. Tools to measure virus persistence on cART Latent infection Productive infection HIV DNA 2-LTR circles Integrated DNA Infectious Units (IUPM) Cell associated RNA US RNA and MS RNA HIV RNA (SCA) Lewin and Rouzioux, AIDS 2011

  14. What are potential strategies to achieve a cure?

  15. HIV eradication: cure or remission

  16. Sterilising cure: lessons learned Hutter et al., N Engl J Med, 2009; 360:692

  17. Current questions • Was it the transplant alone? • 2 recent reports of “no detectable virus” following allogeneic transplantation with continuous ART • Henrich et al., IAC 2012 • Was it the CCR5D32 transplant? • Is this truly a “sterilising” cure? • Does finding a little bit of virus matter?

  18. Functional cure: elite controllers Strong HIV-specific T-cell responses Long term effects Loss of CD4 (7%) Ongoing virus replication and evolution Immune activation increased ?reduced transmission Long term non-progressors Elite controllers Hunt et al., J Infect Dis 2008 ;197:126; Hatano et al., J Virol 2009; 83: 329; Pereyra et al., J Infect Dis 2009; 200:984; HIV Controller Study, Science. 2010;330(6010):1551-7 Soghoian DZ et al., Sci Transl Med 2012; 4(123):123ra25; Hersberger et al., Blood. 2011;117(14):3799-808

  19. Functional cure: post cART controllers VisORA02 9 10 2000 8 10 7 10 6 1500 10 5 10 RNA copies/ml CD4+ T cells/mm3 4 1000 10 3 10 2 10 500 1 10 0 10 0 01 02 03 04 05 06 07 08 09 10 Year VISCONTI cohort; n=12, treated in acute infection; median times since treatment interruption 72 months Hocqueloux et al., AIDS 2010; Salgado et al., Retrovirology 2011; 8:97; Saez-Cirion et al (unpublished)

  20. Post cART controllers do not have favorable HLA types 80 HLA B35 HLA B27 60 HLA B57 40 % of patients 20 0 Chronic HIV Acute HIV Elite controllers Post ART controllers Saez-Cirion et al, unpublished

  21. Strategies for cure Eliminate latently infected cells Eliminate residual virus replication Enhance HIV-specific immunity Make cells “resistant” to HIV

  22. current clinical trials:eliminate latently infected cells

  23. Eliminate latently infected T-cells: activate latent HIV cART Resting CD4+ T-cell Activated CD4+ T-cell

  24. Histone deacetylase (HDAC) inhibitors1, 2 Cytokines IL-73,4 IL-155 Anti-alcohol agent Disulfuram6 Methylation inhibitors 5-aza-dC7 Immune modulation Anti PD1 NF-kB activators Prostratin, PMA, TNF4 Akt/HEXIM-1 modulators HMBA8 Histone Methyltransferase inhibitors (HMTI)9 Chaetocin, BIX-01294 Other Quinolines10 Combination enhances potency4,9,11 Activating latent HIV: in vitro    1Contreras, J Biol Chem. 2009;284(11):6782-9; 2Wightman., Immunol Cell Biol 2012; 3Wang, J Clin Invest 2005; 115:128; 4Saleh, Retrovirology 2011;8:80; 5Chomont, 6thIAS Rome 2011; 6Xing, J Virol; 2011;85(12):6060-4; 7Friedman, J Virol;2011 85:9078-8; 8Contreras PLoS Pathog. 2007 3(10):1459-69 ; 466-72; 9Bouchat, AIDS 2012; 10Xing et al., J Antimicrob Chemother. 2012;67(2):398-403; 11Reuse et al., PLos One 2009;4:e6093

  25. HDACi turn HIV genes “on” HDACi TF OFF 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; Reuse et al., PLos One 2009;4:e6093; Burnett et al., J Virol 2010: 84: 5958-5974;

  26. Vorinostat (SAHA) • Potent HDAC inhibitor • Activates HIV from latency in vitro • Licensed for cutaneous T cell lymphoma • Multiple phase II trials for other malignancies • Short term toxicities well described • Long term toxicities unknown (AMES positive) Contreras et al, J Biol Chem 2009; 284: 6782; Archin et al AIDS Res Hum Retroviruses 2009;25:207; Saleh et al., Retrovirology 2011;8:80; Wightman et al Immunol Cell Biol 2012 Jan;90(1):47-54; Prince et al. Clin Canc Res 2009;15:3958

  27. n=20 day 0 14 84 cART>3 years HIV RNA<50 c/ml CD4>500 cells/ml cART Vorinostat 400 mg/day * Rectal biopsy * * Lewin, 19th CROI, Seattle 2012, abstract #106 1 2 3 4 5 n = up to 20 visit cART > 6 months HIV RNA < 50 c/ml CD4 > 300 cells/ml In vitro response to vorinostat cART * PK * 400mg 200mg 400mg * Leukapharesis (post dose as per PK) Archin et al., 19th CROI, Seattle 2012, abstract #157LB Activating latent HIV: HDACi vorinostat

  28. Vorinostat turns HIV genes “on” in vivo 800 Baseline cART Vorinostat 400 mg 600 400 HIV-1 gag RNA copies per well 200 60 40 20 0 Pt. 1 Pt. 2 Pt. 3 Pt. 4 Pt. 5 Pt. 6 Archin et al., 19th CROI, Seattle 2012, abstract #157LB

  29. Activating latent HIV: disulfiram 0 3 7 14 84 10 n=20 day cART>18 months HIV RNA<40 c/ml CD4>200 cells/ml cART * * Disulfiram 500 mg/day * IUPM (infectious units per million cells) • Significant increase in • HIV RNA in plasma on disulfiram (p>0.001) • No significant decrease • in IUPM Pre-DIS Post-DIS DIS Spivak et al, 19th CROI, Seattle 2012, abstract 369

  30. Will latently infected T-cells die post activation? cART Cytotoxic T-cells Resting CD4+ T-cell + Shan et al., Immunity 2012; 36:1-11 Activated CD4+ T-cell ?

  31. Latently infected cells are rare

  32. current clinical trials:eliminating virus replication

  33. Eliminating viral replication: no effect of treatment intensification T20 LPV/r ATV/r Raltegravir (x5) Maraviroc (x3) Dinoso et al., Proc Natl Acad Sci U S A, 2009. 106(23): 9403; McMahon et al., Clin Infect Dis, 2010. 50: 912; Ghandi et al., J Infect Dis. 2010.201:293; Buzon et al., Nat Med, 2010 16: 460; Ghandi et al., Plos Med 2011;7 Yukl et al., AIDS 2010;16:2451; Hatano et al., J Infect Dis 2011; 203:960; Gutierrez, Plos One 2011:12:e27864 HIV RNA HIV DNA 50 1 0 1 Years on cART intensification

  34. week 0 8 28 32 56 n=29 cART Arm A +intensification (raltegravir +maraviroc) cART ERAMUNE 01 EUROPE Arm B +intensification (raltegravir +maraviroc) IL-7 n=28 cART Arm A +intensification (raltegravir +maraviroc) ERAMUNE 02 US cART Arm B +intensification (raltegravir +maraviroc) DNA prime HIV Ad5 ERAMUNE: treatment intensification, activation and enhance immunity Primary endpoint – HIV DNA in PBMC

  35. Eliminating viral replication: the need to go beyond cART • Reduce immune activation1 • Mesalamine (UCSF) • Rifaximin (ACTG) • ACE inhibitors (lisinopril; UCSF/amfAR) • Methotrexate (ACTG) • Enhance tissue/cell delivery • Nanoparticles2 • Pro-drugs eg., GS-73403 • Target cells of the myeloid lineage 1Clinical trials.gov; 2Kovochich et al., Plos One 2011; 6: e18270; 3 Ruane et al., 19th CROI Seattle #103

  36. current clinical trials:making cells resistant to HIV

  37. CCR5 Nucleases chop up DNA: eliminate CCR5 expression 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; Tebas et al., 18th CROI, Boston, Feb 2011 abstract 165

  38. Conclusions • Multiple barriers to eradication means a combination approach will be likely • Strategies being tested in early proof of concept studies including activating latency, gene therapy, vaccination ± intensification • Engagement of community, regulatory bodies, and pharmaceutical companies will be critical to advance the field • Significant ethical issues and additional challenge to find a strategy that ultimately is cheap, scalable and widely available

  39. Department of Medicine, Monash University Paul Cameron Suha Saleh Ajantha Solomon Fiona Wightman Miranda Smith Pushparaj Velaydham Gabriela Khoury Vanessa Evans Nitasha Kumar Jenny Anderson Hao Lu The Alfred Julian Elliott Jennifer Hoy Janine Roney James McMahon National Association of People living With AIDS Jo Watson Bill Whittaker Peter Macallum Institute Miles Prince Ricky Johnston Others Steve Deeks Hiroyu Hatano Christine Katlama Brigitte Autran Christine Rouzioux Acknowledgements

More Related