Toward A Cure for HIV Plenary Lunch Keynote Dr. Sharon Lewin Head, Department of Infectious Diseases Alfred Hospital and Monash University

Finding a cure for HIV: the need for science, advocacy and collaboration Sharon R Lewin Director, Infectious Disease Unit, Alfred Hospital Professor, Department of Medicine, Monash University Co-head, Centre for Virology, Burnet Institute, Melbourne, Australia US Conference on AIDS, Las Vegas, October 1st., 2012 Thank you Dr Whitescarver for the kind introduction and a special thank you to Paul Kuwata for inviting me to address to you today – not only a pivotal time in the HIV/AIDS epidemic but also a very exciting time when scientists, clinician and communities should no longer be hesitant to say the words “HIV Cure” and a time where “finding a cure” is rapidly becoming a major priority on the research agenda

Over the past 12-18 months, we have all be tremendously excited about the growing momentum and commitment to end AIDS or at least see an AIDS free generation in you and my life time

The end of AIDS? seek, test and treat prevention cure Some think that the end of AIDS might be possible by treatment alone. The results of HPTN 052 have unequivocally shown us that treatment significantly reduces transmission – so finding, testing and treating everyone could potentially work. IT’s a very expensive option but is an approach we must continue to advocate for. Prevention of any new infections may also one day be achievable with the demonstrated success of PREP, microbicides and hopefully one day an effective vaccine. However, the third and critical component of ever seeing an end not just to AIDS, but and end to HIV, is to find a cure. Even if we had an effective vaccine tomorrow, there are 33 million infected with HIV, all who need to reliably access and adhere life long treatment

Why we need a cure for HIV Life expectancy remains reduced and ongoing morbidity on cART For every 2 new patients who initiate cART there are 5 new infections Globally, only 60% of patients who need cART are being treated Funding lifelong cART for all who need it is unlikely to be sustainable

Outline What are the major barriers to cure? What type of cure might be achieved? What is being tested in clinical trials? Current and future challenges in HIV cure research

what are the major barriers to cure?

Virus persists in all patients on cART Tissue Cell associated HIV DNA Cell associated HIV RNA Blood Cell associated HIV RNA Infectious virus (IUPM) Cell associated HIV DNA HIV RNA 50 Plasma single copy assay 1 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; 8 8

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 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 Resting CD4+ T-cell HIV latency

Latently infected T-cells cART

Residual replication cART

Anatomical reservoirs

What type of cure might be achieved?

HIV eradication: cure or remission Infectious Diseases model Cancer model Elimination of all HIV-infected cells Long term health in absence of cART HIV RNA < 1 copy/ml HIV RNA < 50 copies/ml Sterilising cure Functional cure

Timothy Brown and Matt Sharp

Sterilising cure: transplantation of “HIV resistant” bone marrow scBMT (X2) Donor CCR5– (DD32) Chemotherapy (x4) Total-body irradiation (x2) “CCR5–” off cART no viral rebound “sterilising cure” cART CCR5+ (WT) HIV+ Leukemia (AML)

Sterilising cure: lessons learned Bone marrow transplantation 2nd bone marrow transplantation AML diagnosis cART cART 107 GI tract biopsy CSF Brain biopsy 106 105 Plasma RNA +/- GI tract DNA +/- ? significance HIV-1 RNA (copy/mL) 104 103 102 2007 2008 2012 Hutter et al., N Engl J Med, 2009; 360:692; Allers et al., Blood. 2010 117(10):2791; Yukl et al., International Workshop on HIV and Hepatitis Resistance, Sitges, June 2012

Could allogeneic transplantation be enough? BMT CCR5+ (WT) Reduced intensity irradiation (RISC) HIV+ Lymphoma (n=2) CCR5+ (heterozygous) cART HIV DNA neg HIV RNA neg (2-4 yrs post Tx) Henrich et al., XIXth IAC, Washington DC, July 2012

Functional cure: elite controllers Strong HIV-specific T-cell responses Enriched for “protective” HLA types Long term effects Loss of CD4 (7%) Ongoing virus replication and evolution Immune activation increased Long term non-progressors Elite Controllers VL<50c/ml 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

Functional cure: post cART controllers CASCADE cohort; Europe and Aust; n=259 treated in acute infection and ceased cART VISCONTI cohort n=14, France treated in acute infection median time on ART =37 months; median times since stopping ART = 80 months “Unique” immunological profile <5.5% Hocqueloux et al., AIDS 2010; 2010;24(10):1598; Goujard et al., Antiviral Therapy 2012;17:1001; Lodi et al., Arch Int Med 2012; 172(16):1252; Saez-Cirion et al., XIXth IAC, Washington DC, July 2012

What “cure” do PLWHA want? No ART Not infectious Never get HIV again Option 1  Option 2 potentially Option 3 Option 4 Highly desirable Somewhat desirable 95% 5 41% 27% 24% 32% 19% 32% Survey of Dutch PLWHA; N=458 (46% of respondents) Verdult, F, IAS HIV Cure Workshop, Washington DC, July 20-21, 2012

Strategies to achieve a cure Eliminate latently infected cells Eliminate residual virus replication Enhance HIV-specific immunity Make cells “resistant” to HIV

current clinical trials: eliminating latently infected cells

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

Activating latent HIV: in vitro 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 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, 6th IAS 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

Activating latent HIV: HDACi vorinostat * cART Vorinostat 400 mg/day 14 84 Australia; n=20 Rectal biopsy day cART>3 years HIV RNA<50 c/ml CD4>500 cells/ml 7 1 3 cART 200mg 400mg 2 4 3 US; n = up to 20 Leukapharesis (post dose as per PK) * visit cART > 6 months HIV RNA < 50 c/ml CD4 > 300 cells/ml In vitro response to vorinostat 1 5 PK Archin et al., Nature 2012; 487: 482

Vorinostat turns HIV genes “on” in vivo Baseline cART Vorinostat 400 mg 800 600 400 200 60 40 20 Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Relative HIV-1 gag copies 100 Pt 7 Pt 8 Cell associated RNA quantified in resting CD4+ T-cells (mean of 20-30 replicates) Archin et al., Nature 2012; 487: 482

Trials of other latency “activating” agents Design PI (location) Status HDACi Vorinostat 14 days 400 mg/day Lewin (Australia) Fully enrolled Panobinostat 3 x /week x4 Ostergard (Denmark) Enrolling Rhomedepsin Single dose ACTG (US) In discussion Cytokine IL-7 3 doses +intensification Katlama (Europe) Other Disulfiram 500 mg/day Deeks (US) Ongoing 3 days dose escalation Elliot/Lewin (Australia) Submitted Anti-PD-1

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

Latently infected cells are rare

current clinical trials: eliminating virus replication

Eliminating viral replication: no effect of treatment intensification 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 T20 LPV/r ATV/r Raltegravir (x5) Maraviroc (x3) HIV RNA HIV DNA 50 1 1 Years on cART intensification 34 34

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

current clinical trials: making cells resistant to HIV

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

Gene therapy to eliminate CCR5 Inclusion criteria n NCT01044564 (PI Tang, Sangamo; 5 cohorts) Dose escalation 3 x 3 cART failure 4 CCR5D32 hetero 20* NCT00842634 (PI Tebas, Sangamo; 3 cohorts) 6 Stable cART 6* Poor CD4 recovery NCT01252641 (PI Tang, Sangamo) No cART 30 * Treatment interruption Lalezari et al., 18th CROI, Boston, 2011

current and future challenges in HIV cure research

Scientific challenges Multiple barriers to eradication means a combination approach will be likely Standardised, non-invasive assays to quantify viral reservoirs in vivo for multi-site clinical trials Drug development to increase specificity for latently infected cells, enhance tissue delivery and reduce toxicities Better understanding of the immune system in controlling low level viremia and latent infection

Ethical considerations What are acceptable risks and toxicities of interventions in a population doing well on stable cART? What marker(s) of viral persistence will justify treatment interruption as a clinical endpoint in subsequent clinical trials? Expectations of study participants in early “proof of concept” studies. Community literacy and engagement is critical Universal access to cART must remain a top priority

science, collaboration and advocacy

Funding cure research

Towards an HIV Cure: a global scientific strategy launched July 2012

An integrated strategy Int’l scientific collaborations Interaction between Basic + Clinical Science Data exchange platforms between pilot studies New concepts, new generation Cross-talk with other scientific disciplines Cooperation public + privates sectors Community engagement Funding

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

Acknowledgements National Association of People living With AIDS 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 Christine Katlama Brigitte Autran Christine Rouzioux Dan Kuritzes Javier Picado Martinez

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