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Latency reversing agents

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

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

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

5 Transient “remission” is possible
Two Boston Patients1,2 The Mississippi Child3 Treatment CCR5+/+ bone marrow transplant Early ART Remission off ART 3 months and 7 months 2.5 years Lesson Delayed 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 Aiming for sustained “remission” off ART
Cohen J. Science 2014 July

7 Latently infected T-cells
cART Homeostatic proliferation

8 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. 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. Intermittent bursts of viremia originate in part from this latent reservoir. Forcing these cells to exit the latent state without enhancing new infection could make the virus vulnerable to clearance by an HIV-targeted immune response. Blocking the proliferation of these latently infected T cells could deplete the pool if its stability is driven by such multiplication. Science 2014

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 A model using the exposure to viremia over time in early infection predicts the frequency of latent infection (“…size of the reservoir…”) Archin et al. 2012

12 Very early ART significantly reduces reservoir size
14% 74% 100% Duration of HIV before ART N Ananworanich et al, 20th International AIDS Conference AIDS2014, Melbourne, Australia, 2014

13 Very early ART reduces reservoirs but…rebound still occurs in SIV
Time to viral rebound, days Log HIV DNA in PBMC Day of ART initiation post infection 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
latent virus Boston patients Mississippi child VISCONTI patients (EM>CM) ? Lewin SR. Ann Int Med 2014 July 22

15 Activating latent HIV The Economist, July 17, 2011

16 A first step to eliminate latent HIV infection
A second step to eliminate latent HIV infection Immunotherapy Anti-latency therapy Current paradigm that is beginning to be tested Other Challenges: Clearance of infected cells Clearance of virions Complete block of new infection

17 Activating latent infection: in vitro
“activate” HIV US RNA HIV DNA HIV proteins HIV virions HIV DNA Cell death Latent infection HDACi Methylation inh Cytokines eg., IL7 disulfiram quinolines Histone methyl transf inh BET inh

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

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

20 Histone deacetylase inhibitors turn HIV genes “on”

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

22 HDACi: activity in cancer and HIV
Clinical development HIV latency Vorinostat Pan HDACi Licensed - CTCL Single dose1 Intermittent2 Continuous3 Panobinostat Phase III – multiple myeloma Intermittent dose4 Romedepsin Class I HDACi Weekly dose5 Entinostat Phase III – breast cancer TBD6 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; 3Elliott J et al., Plos Pathogens 2014 (in press); 4Rasmussen et al., Lancet HIV 2014; epub Sept 16; 5Sogaard et al., 20th International AIDS Conference (AIDS2014), Melbourne, 2014; 6Wightman et al., AIDS Nov 28;27(18):

23 A single dose of HDACi vorinostat activates HIV transcription in vivo
Baseline cART 800 600 400 200 60 40 20 Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Pt 6 Relative HIV-1 gag RNA copies 100 Pt 7 Pt 8 Vorinostat 400 mg Archin et al., Nature 2012; 487: 482

24 Can continuous doses of vorinostat “activate” latent infection?
day 1 3 7 14 21 28 84 cART>3 years HIV RNA<50 c/ml CD4>500 cells/ml cART Vorinostat 400 mg/day * Rectal biopsy * * Single site, single arm, non-randomised observational study Elliott et al., Plos Pathogens 2014

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

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

27 Panobinostat: a more potent HDACi
cART M/W/F 28 49 n=16 day cART>3 years HIV RNA<50 c/ml CD4>350 cells/ml 21 7 14 35 42 Panobinostat 20mg/day, 3 times a week (Monday, Wednesday, Friday)

28 The HDACi panobinostat activates latent HIV and produces some virus
Fold increase in CA-US RNA ANOVA p<0.0001 days 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
HIV RNA in plasma, copies/ml Days post first infusion No change in HIV DNA following romidepsin x 3 Sogaard et al., 20th International AIDS Conference, Melbourne, 2014

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 QVOA growing virus The “Real” Reservoir

34 Where can HIV eradication approaches be tested?

35 When latency is disrupted, mechanisms to kill virus- expressing cells may be needed

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=9 responders 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
Agent Design PI (location) Status HDACi Vorinostat + vaccine 10 days (acute treated HIV) Frater (UK) Approved Rhomedepsin Single dose ACTG (US) Rhomedepsin + vaccine Ostergaard (Denmark) Rhomedepsin alone (complete) Other Disulfiram 14 days 500mg/day Deeks (US) Transient increase in plasma RNA (Spivak CID 2014) 3 days 500mg-2g/day Elliot/Lewin (Australia) Enrolment complete Anti-PDL1 (BMS) Eron (US/ACTG) Enrolling

39 Managing the hope and hype
Danish breakthrough for HIV cure expected 'within months' April 29th, 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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