Viral load // HIV cure research: current strategies and challenges Sharon R Lewin Director, Doherty Institute for Infection and Immunity, The University of Melbourne, Consultant physician, The Alfred, Melbourne, Australia Australasian Society for HIV Medicine; September 6-8 th, ; Brisbane, Australia, Sustained remission off ART is rare but achievable ART -4 weeks Boston A months Boston B 8 months Mississippi child 8 months Visconti, French Teenager Limit of detection Timothy Brown 6 7 years Hütter et al. N Engl J Med 9; Persaud et al. N Engl J Med ; Luzuriaga et al. N Engl J Med ; Henrich et al. Ann Intern Med 4; Saez-Cirion et al. Plos Path ; Saez-Crion et al., IAS, Vancouver ;. Barriers to cure Latently infected T-cells Residual viral replication current strategies to eliminate latently infected cells Anatomical reservoirs Eliminating latently infected cells Early ART limits persistence of HIV reservoir in all CD4+ T cell subsets Treatment during acute infection Activating latent infection Boosting HIV-specific immunity FI: +, HIV IgM- FIII: HIV IgM+, WB- Allogeneic transplantation Reducing homeostatic proliferation(?) After years of ART, integrated is undetectable in all subsets of Fiebig I individuals. Nicolas Chomont and Jintanat Ananworanich
M S H IV R N A (F C o v e r D M S O ) S S H IV R N A (F C o v e r D M S O ) // Post treatment control is rare following ART in acute infection Published studies n endpoint % Optiprim (Cheret A, Lancet ID ) Spartac (Stohr W, Plos One ) VISCONTI (Saez-Cirion A, Plos Pathogens ) Swiss HIV Cohort Study (Gianella S, Antiviral Therapy ) Primo-SHM (Grijsen ML, PLoS Medicine ) ANRS CO6 PRIMO (Goujard C, Antiviral Ther ) CASCADE (Lodi S, Arch Intern Med ) 9 < years 6 <4 years 4 < 6 years < year 7 <. year 64 < / year /9 9 < / year 8/ Ananworanich, Keystone Symposium on HIV cure, April 9 We need a biomarker that can predict cure or remission : SPARTAC, Swiss HIV Cohort Study CA-US HIV : ACTG ATI Cohort Study PD expression on CD4 and CD8 (prior to ART): SPARTAC Activating latent infection Latency reversing agents: many now in clinical trials shock HIV US HIV proteins Epigenetic modifiers HDACi Methylation inhibitors Methyltransferase inhibitor Bromodomain inh TLR agonists TLR7 (GS96) TLR (polyiclc) TLR 9 TLR4 Latent infection HIV virions Cell death Activators of NF-kB Prostratin Bryostatin Ingenol B / PEP SMAC mimetics Other Disulfiram Quinolines IL- HDACi activate HIV latency in vivo Adverse effects on HIV splicing following activation with potent HDACi HDACi Clinical development Vorinostat Licensed (6) CTCL HIV latency US HIV Plasma Single dose Intermittent Continuous Multiply spliced HIV M S H IV R N A * * * * * * S S H I * * * Panobinostat Licensed () multiple myeloma Intermittent dose 4 +/- Romedepsin Licensed (9) CTCL Weekly dose. 6 4 4 8 7 6 4 4 8 7 6 4 4 8 7 6 4 4 8 7 V O R R M D J Q P M A /P H A. 6 4 4 8 7 6 4 4 8 7 V O R R M D Changes over time for each LRA: Kruskal-Wallis; *** p.; **** p. Talia Mota Archin et al., Nature ; Archin et al., J Infect Dis 4; Elliott J et al., Plos Pathogens 4; 4 Rasmussen et al., Lancet HIV 4; Sogaard et al., Plos Pathogens (in press) CTCL cutaneous T-cell lymphoma HDACi have adverse effects on HIV-specific immunity (in vitro) and host gene changes Jones et al., Plos Path 4; Elliott et al, Plos Path 4
P la s m a S IV R N A C D 8 + C D 6 9 + ly m p h o c y te s (lo g c o p ie s /m L ) C h a n g e fro m p r e -d o s e (% ) 4 - - - - / / / / / / / / / / / / 7 4 6 7 8 9 4 4 44 4 49 6 7 8 9 6 7 7 7 7 77 84 8 86 87 9 D ays after first TLR 7 agonist dose * * / / / / / / / / / / / / 7 4 6 7 8 9 4 4 44 4 49 6 7 8 9 64 7 7 7 7 77 84 8 86 87 9 D ays after first TLR 7 agonist dose A s s a y D e te c tio n L im it c o p ie s /m L D o s e (m g /k g ) D o s e (# )....... D o s e (m g /k g ) 4 6 7 D o s e (# ) // TLR7 agonist activates HIV latency in SIV infected macaques Disulfiram dose escalatiotudy to activate HIV latency Plasma SIV....... 4 6 7 CD8 T cell activation Human clinical trial of a similar TLR7 agonist currently enrolling Whitney et al., CROI, Seattle Elliott JH et al., CROI, Seattle. Abstract 48LB High dose disulfiram increases cell associated and plasma HIV Activation of non-canonical NFKB pathways: synergism with HDACi Resting CD4+ T-cells from individuals on ART A modest ( fold) but significant increase in cell associated and plasma HIV with disulfiram g/day Elliott JH et al., CROI, Seattle. Abstract 48LB Pache et al., Cell Host Microbe Boosting HIV-specific immunity Therapeutic vaccination: bnabs and CMV vaccine shock (tickle) and kill shock HIV proteins kill Combination cure studies Romedepsin + Vacc x4 Romdepsin + BNC7 HIV US Latent infection HIV virions Cell death reduce and control Phase humatudies to start in 6
// B cell follicles in lymph node might be a barrier ALT-8 (IL superagonist) acts an an LRA and boosts CTL Ex vivo model using million resting CD4+ T-cells (6 billion PBMC) from patients on ART co-cultured with autologous CTL Brad Jones et al., Keystone Symposium on HIV Cure, Boston, MA, April Blocking immune checkpoint markers to boost immune function Combination immune checkpoint blockade: greater efficacy in melanoma CTLA-4 TIGIT TIM- Role in HIV infection? Drug Company Target Registration HIV Nivolumab BMS PD- FDA approved: melanoma no Pembrolizumab Merck PD- FDA approved: melanoma and lung cancer no BMS-969 BMS PD-L Phase III: solid organ malignancy On hold Ipilimumab BMS CTLA-4 FDA approved: melanoma Case reports Wightman et al., AIDS ;9(4):4-6 Gene therapy: ZFNs to knockout CCR making cells resistant to HIV T cells or HSC CCR ZFNs - m electroporation Return to patient Trials update: Several Phase I/II trials ongoing modifying T cells (NCT4, NCT66, NCT8894) First HSC trial anticipated opening July 4
SSC // Targeted nucleases allow precise gene editing or site-specific gene addition Conclusion Ctrl. CCR ZFN m + AAV-GFP donor 9% Several interventions have beehown to significantly reduce the frequency of latently infected cells including very early ART and transplantation but this rarely translates into prolonged remission GFP GFP insertion at CCR in HSC Beyond gene (CCR) knockout, this opens up the possibility of editing host genes such as restriction factors, or inserting anti-hiv genes at a specific site Activation of latent HIV possible in vivo with HDACi, disulfiram and TLR7 agonists but remains a need for more potent, less toxic and more specific LRAs Combination activation and/or enhanced immunity through vaccination or immune check point inhibition currently being evaluated Knock out or knock in gene therapy may play a role Acknowledgements Doherty Institute, Uni Melb Paul Cameron Suha Saleh Jenny Anderson Fiona Wightman Ajantha Solomon Christina Chang Karey Cheong Surekha Tennakoon Hao Lu Ashanti Dantanarayana Renee Van der Sluis Vanessa Evans Talia Mota Damien Purcell Julia Stout Jennifer Audsley The Alfred Hospital Julian Elliott James McMahon Jennifer Hoy Janine Roney Michelle Bogliss The Burnet Institute Project Inform Melissa Churchill David Evans Lachlan Gray NAPWHA Tim Spelman Cipri Martinez NCI Frederick Jo Watson Jeff Lifson Bill Whittaker Robert Gorelisk Others Mike Piatak UCSF, San Francisco Jintanat Ananworanich Steven Deeks Brad Jones Rebecca Hoh Sulggi Lee Wendy Hartogenesis Peter Bacchetti Marian Kerbleski Elizabeth Sinclair Teri Liegler Rada Savic Rick Hecht Johns Hopkins University Robert Siliciano Namandje Bumpus University of Montreal Nicolas Chomont Remi Fromentin