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LATENCY REVERSING AGENTS HIV Cure Research Training Curriculum Latency Reversing Agents Module by: Scientific Leads: David M. Margolis (CARE) and Sharon.

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Presentation on theme: "LATENCY REVERSING AGENTS HIV Cure Research Training Curriculum Latency Reversing Agents Module by: Scientific Leads: David M. Margolis (CARE) and Sharon."— Presentation transcript:

1 LATENCY REVERSING AGENTS HIV Cure Research Training Curriculum Latency Reversing Agents Module by: Scientific Leads: David M. Margolis (CARE) and Sharon Lewin (DARE) Community Leads: Cipri Martinez (DARE) and David Palm (CARE) The HIV CURE training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field.

2 US military cohort (n = 2327, mean age 35) who started ART after 2000, 5-year mortality 0.3% Marconi 2010 Predicted survival if HIV+ at 25 yrs

3 Combination HIV Prevention Reduce the number of new HIV infections Treatments that clear Infection Reduce the number of HIV-infected people

4 Prevention Diagnosis TreatmentCure Last public appearance of the entire AIDS Quilt, 1996Prevention Diagnosis Treatment

5 Transient “remission” is possible Two Boston Patients 1,2 The Mississippi Child 3 TreatmentCCR5+/+ bone marrow transplant Early ART Remission off ART 3 months and 7 months 2.5 years LessonDelayed viral rebound is achievable But unknown biomarkers for HIV remission Henrich et al., J Infect Dis 2013, 207(11): Henrich et al., Ann Intern Med Jul 22; Persaud et al., N Engl J Med 2013 Nov 7;369(19):

6 Cohen J. Science 2014 July Aiming for sustained “remission” off ART

7 Latently infected T-cells cART Homeostatic proliferation

8 Science 2014 The persistent pool of HIV-1 antiretroviral therapy can prevent the creation of new latently infected cells, but it does not affect cells in which latency was initially established.

9 Residual viral expression cART Evidence for residual viral expression in about one third of patients on cART Buzon et al., Nature Med 2010; 16: 460; Hatano et al, J Infect Dis 2013

10 Anatomical reservoirs

11 Archin et al A model using the exposure to viremia over time in early infection predicts the frequency of latent infection (“…size of the reservoir…”)

12 Ananworanich et al, 20 th International AIDS Conference AIDS2014, Melbourne, Australia, 2014 N % 74% 14% Duration of HIV before ART Very early ART significantly reduces reservoir size

13 Very early ART reduces reservoirs but…rebound still occurs in SIV Day of ART initiation post infection Log HIV DNA in PBMC Time to viral rebound, days N=20, SIVmac251 infected macaques treated with tenofovir/FTC/dolutegravir for 24W Whitney et al., Nature 2014, July 20

14 Balance between reservoir and immunity immunity latent virus Lewin SR. Ann Int Med 2014 July 22 Boston patients Mississippi child VISCONTI patients (EM>CM) ?

15 Activating latent HIV The Economist, July 17, 2011

16 Other Challenges: Clearance of infected cells Clearance of virions Complete block of new infection A first step to eliminate latent HIV infection Anti-latency therapy A second step to eliminate latent HIV infection Immunotherapy

17 HIV DNA HIV US RNA HIV DNA HIV proteins HIV virions Latent infection “activate” Cell death HDACi Methylation inh Cytokines eg., IL7disulfiramquinolines Histone methyl transf inhBET inh Activating latent infection: in vitro

18 Latently infected cell lines e.g., J-Lat, ACH2, U1 Constantly dividing Clonal Integrate in heterochromatin Latently infected primary T-cells Resting cells High frequency of latency Pre and post activation models Resting CD4+ T-cells from HIV-infected patients on ART Often needs leukapharesis Frequency of latency low Mechanistic studies difficult Highly variable responses Identifying latency reversing agents (LRA) in vitro

19 T-cell activationPKCCytokinesHDACiothe r Spina et al., Plos Pathogens 2013 Dec;9(12):e No model ideally represents latently infected ells from patients

20 TF OFF HDACi Histone deacetylase inhibitors turn HIV genes “on”

21 HIV DNA HIV US RNA HIV DNA HIV proteins HIV virions Latent infection “activate” Cell death cART Latency “activating” agent cART>3 years HIV RNA<50 c/ml CD4>350 cells/ml Activating latent infection: clinical trials

22 HDACiActivityClinical developmentHIV latency VorinostatPan HDACiLicensed - CTCLSingle dose 1 Intermittent 2 Continuous 3 PanobinostatPan HDACiPhase III – multiple myeloma Intermittent dose 4 RomedepsinClass I HDACiLicensed - CTCLWeekly dose 5 EntinostatClass I HDACiPhase III – breast cancer TBD 6 CTCL – cutaneous T-cell lymphoma 1 Archin et al., Nature 2012; 487: 482–85; 2 Archin et al., J Infect Dis 2014; 210: 728–35; 3 Elliott J et al., Plos Pathogens 2014 (in press); 4 Rasmussen et al., Lancet HIV 2014; epub Sept 16; 5 Sogaard et al., 20 th International AIDS Conference (AIDS2014), Melbourne, 2014; 6 Wightman et al., AIDS Nov 28;27(18): HDACi: activity in cancer and HIV

23 Baseline cART Vorinostat 400 mg Archin et al., Nature 2012; 487: Pt 1Pt 2Pt 3Pt 4Pt 5Pt 6 Relative HIV-1 gag RNA copies 100 Pt 7 Pt 8 A single dose of HDACi vorinostat activates HIV transcription in vivo

24 * * cART Vorinostat 400 mg/day 01484n=20 Rectal biopsy * day cART>3 years HIV RNA<50 c/ml CD4>500 cells/ml Single site, single arm, non-randomised observational study Elliott et al., Plos Pathogens 2014 Can continuous doses of vorinostat “activate” latent infection?

25 Fold increase CA-US HIV RNA above baseline Median fold change max = 7.4 (IQR 3.4, 9.1) Elliott et al., Plos Pathogens 2014 Vorinostat induces a significant increase in unspliced HIV RNA

26 But…no change in plasma HIV RNA or HIV DNA

27 Panobinostat: a more potent HDACi cART M/W/F 02849n=16day cART>3 years HIV RNA<50 c/ml CD4>350 cells/ml M/W/F Panobinostat 20mg/day, 3 times a week (Monday, Wednesday, Friday)

28 The HDACi panobinostat activates latent HIV and produces some virus days Fold increase in CA-US RNA ANOVA p< Some increase in virus in plasma in some patients No change in the reservoir ie no change in HIV DNA Rasmussen et al., Lancet HIV 2014

29 The HDACi romidepsin is more potent and activates virus release Sogaard et al., 20 th International AIDS Conference, Melbourne, 2014 No change in HIV DNA following romidepsin x 3 romidepsin HIV RNA in plasma, copies/ml Days post first infusion

30 What we have found so far: A single dose of VOR induces expression of full- length HIV RNA within latently infected resting CD4+ T cells. The optimal dosing schedule of VOR, and its ability to repeatedly and completely perturb latency in all relevant infected cells, must be established Separately, the potential for VOR to induce antigen expression in (some or all) latently infected cells must be established

31 Will HDACi be enough? Not all studies show induction of viral expression by HDACi ex vivo Combinations of anti-latency compounds with different mechanism of action may be more effective Latently infected cells that express HIV-1 RNA may not all die

32 Latently infected cells are rare

33 HIV DNA, RNA, antigen & viruses HIV Antigen (protein) detector The “Real” Reservoir HIV DNA QVOA growing virus

34 Where can HIV eradication approaches be tested? “HUMANIZED” MICE

35 When latency is disrupted, mechanisms to kill virus- expressing cells may be needed AUGMENT HIV-1 SPECIFIC IMMUNE RESPONSE WITH HIV-1 VACCINE PRIOR TO “KICK” IMPROVE HIV-1 SPECIFIC CD8 RESPONSE THROUGH EX VIVO MANIPULATION EXPANSION or TCR ENHANCEMENT Wake up “exhausted” HIV-1 specific cells eg. Checkpoint inhibitors Dual function Ab to recruit immune effectors without the need for HIV-specific cells INFUSE BROADLY NEUTRALIZING ANTIBODY OR ANTIBODY PRIMED FOR ADCC

36 Blocking PD1-PDL1 to boost immune function Mason et al., CROI 2014

37 Anti-PDL1 led to successful virus control following ART in half the monkeys isotype n=5; anti-PDL1 n=9responders n=4, non-responders n=5 ACTG: single infusion of anti PDL-1 (BMS) to start in 2014

38 Current clinical trials to eliminate latently infected cells AgentDesignPI (location)Status HDACi Vorinostat + vaccine 10 days (acute treated HIV) Frater (UK)Approved RhomedepsinSingle doseACTG (US)Approved Rhomedepsin + vaccine Single doseOstergaard (Denmark)Rhomedepsin alone (complete) Other Disulfiram14 days 500mg/day Deeks (US)Transient increase in plasma RNA (Spivak CID 2014) Disulfiram3 days 500mg-2g/day Deeks (US) Elliot/Lewin (Australia) Enrolment complete Anti-PDL1 (BMS)Single doseEron (US/ACTG)Enrolling

39 Managing the hope and hype April 29 th, 2013

40 Expectations of study participants 20 participants with \ HIV infection in vorinostat (HDACi) trial Top priority in cure research (%) McMahon et al., AIDS 2014 (in press)

41 Conclusions We are assembling the tools to design, discover, and test anti-latency therapy Rational design based on biological understanding of latency Screen-based discovery Harnessing the immune response, or other cellular pathways, or new technology to assist in the clearance of persistently infected cells is the next step Developing platforms and novel assays to allow these developments to be efficiently validated, and safely tested in the clinic

42 Acknowledgements

43 Module Collaborators


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