Combining PKC agonists and bromodomain inhibitors to reverse HIV latency
1 October 2015. Related: Cure-related research, Basic science and immunology.
Richard Jefferys, TAG
Two recent papers in PLoS Pathogens report that combinations of candidate latency-reversing agents can potently activate HIV production by latently infected CD4 T cells in laboratory experiments. [1, 2]
Pairings of the PKC agonists bryostatin-1 or ingenol with the bromodomain inhibitor JQ1 were most effective, generating levels of virus production by latently infected cells similar to those achieved by maximal T cell activation.
The results appear consistent with those published earlier this year by the research group of Robert Siliciano at Johns Hopkins University [3], and are encouraging because there had been some scepticism as to whether any latency reversing strategy could match the effects of maximal T cell activation (which is known to be too dangerous to use in people). But there are caveats: the compounds do affect T cell activation pathways and it is not yet known if they will be safe in HIV positive individuals; currently, they are being tested (and in the case of ingenol, used topically) as cancer treatments.
The two new publications derive from independent research laboratories led by Satya Dandekar at UC Davis and Carine Van Lint at Université Libre de Bruxelles (ULB), respectively. The experimental findings are broadly consistent but involve two different variants of ingenol: ingenol-B, which has previously been reported [4] to have latency-reversing activity, and ingenol-3-angelate (PEP005), the active component of an FDA-approved topical treatment for precancerous actinic keratosis named PICATO. The opinions of the two groups regarding which version of ingenol might be safer for systemic use in humans differ somewhat. Van Lint’s group writes: “Importantly, ingenol-3-angelate appears to be more toxic than ing-B when orally delivered to rats and dogs (Luiz Pianowski, Kyolab, Brazil, personal communication).”
While Dandekar states: “Similar to the safety of the topical application of PICATO, the systemic (intravenous) use of PEP005 in small animals (mini pig and rat model) was reported to be relatively safe, with the maximum nonlethal dose >73 μg/kg (See Assessment report of PICATO to European Medicines Agency, Sept 20, 2012) [5]. While additional safety data with systemic administration in non-human primates is needed, these existing data support further investigation of PEP005 as a potential candidate in HIV cure studies.”
Further animal model studies should help resolve this uncertainty. The UK website NHS Choices, [6] which provides commentary on research-related stories in the mainstream media, takes a rather dim view of Dandekar’s suggestion (reported by the BBC) [7] that the FDA-approved status of PICATO is relevant to the prospects of this approach in people with HIV, countering that “although the drug is being used on patients, it is currently just applied to the skin. The effects may be very different if the whole body is exposed to the drug, as would be required to locate hidden reservoirs of HIV.”
The other PKC agonist studied, bryostatin-1, is already being tested in HIV positive people in a small, single-dose clinical trial in Spain [8] supported by a biotech company named Aphios [9]; results are pending. While some researchers have expressed concern about the potential toxicities of bryostatin-1, Van Lint’s group is more sanguine, noting that in a phase I trial in children with cancers (published in 1999) “only few patients have experienced myalgia, photophobia or eye pain.” [10]
But the report from this trial also states “toxicities of bryostatin-1 occurred days after the infusion and lasted for prolonged periods” and I think it’s fair to say that opinions about the acceptability of these types of side effects in healthy HIV positive people are likely to vary. There are ongoing efforts to develop safer and more targeted analogues of bryostatin-1, notably those led by Paul Wender at Stanford University. [11]
Bromodomain inhibitors are also being studied in cancer. The compound used in these studies, JQ1, has too short a half-life for human use but Van Lint and colleagues note: “Clinical trials with JQ1-derivative called TEN-010 (also called JQ2) and another BETi called GSK525762 have been initiated recently to characterise their safety, tolerability, pharmacokinetics and anti-cancer activity (clinicaltrials.gov).” [12]
Safety information from these trials will be important in determining whether studies in HIV are appropriate.
Source:
Jefferys R. Combining PKC agonists and bromodomain inhibitors to reverse HIV latency. TAG basic science blog. (14 Aug 2015).
http://tagbasicscienceproject.typepad.com
References:
- Darcis G, Kula DG et al. An In-Depth Comparison of Latency-Reversing Agent Combinations in Various In Vitro and Ex Vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol-B+JQ1 to Potently Reactivate Viral Gene Expression. PLoS Pathog. 2015 Jul 30;11(7):e1005063. doi: 10.1371/journal.ppat.1005063. eCollection 2015 Jul.
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005063 - Jiang G et al. Synergistic Reactivation of Latent HIV Expression by Ingenol-3-Angelate, PEP005, Targeted NF-kB Signaling in Combination with JQ1 Induced p-TEFb Activation. PLoS Pathog. 2015 Jul 30;11(7):e1005066. doi: 10.1371/journal.ppat.1005066. eCollection 2015 Jul.
http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005066 - Jefferys R. Combining Latency-Reversing Agents, and Reviewing Methods of Measuring the Latent HIV Reservoir. TAG basic science blog. (16 Apr 2015).
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2015/04/combining-latency-reversing-agents-and-reviewing-methods-of-measuring-the-latent-hiv-reservoir.html - Jefferys R. New HIV Latency-Reversing Agent Emerges from the Shrubbery. TAG basic science blog. (26 Aug 2014).
http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2014/08/new-hiv-latency-reversing-agent-emerges-from-the-shrubbery.html - EMA CHMP Assessment report (20 September 2012).
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002275/WC500135329.pdf (PDF) - NHS choices. Hiding HIV virus ‘flushed out’ by skin cancer drug. (03 Aug 2015).
http://www.nhs.uk/news/2015/08August/Pages/hiv-flushed-out-by-skin-cancer-drug.aspx - Gallagher J. HIV flushed out by cancer drug. BBC news. (31 July 2015).
http://www.bbc.com/news/health-33720325 - Clincaltrials.gov. Bryostatin-1 Effect on HIV-1 Latency and Reservoir in HIV-1 Infected Patients Receiving Antiretroviral Treatment (BRYOLAT).
https://clinicaltrials.gov/ct2/show/NCT02269605 - Aphios press news. Aphios completes enrollment in phase I/II clinical trial towards an HIV cure. (2 June 2015).
http://www.aphios.com/news-and-current-events/press-releases-and-news/259-aphios-completes-enrollment-in-phase-i-ii-clinical-trial-towards-an-hiv-cure.html - Weitman S et al. A phase I trial of bryostatin-1 in children with refractory solid tumors: a paediatric oncology group study. Clin Cancer Res 1999;5:2344-2348.
http://clincancerres.aacrjournals.org/content/5/9/2344.full.pdf (PDF) - DeChristopherBA.Designed,syntheticallyaccessiblebryostatinanaloguespotentlyinduceactivationoflatentHIVreservoirsinvitro.NatChem.2012 Sep; 4(9): 705–710.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428736 - https://clinicaltrials.gov