HIV anti Latency Agents Pipeline
This report is part of a series of focused summaries from the “5th International Workshop on HIV Persistence, Reservoirs & Eradication Strategies” held in St Maarten, December 6-9, 2011. It relates oral presentations given by Romas Geleziunas, on behalf of Gilead, and Roger Sutmuller, on behalf of Janssen on the search for new therapeutic strategies targeting latent HIV reservoirs.
The 2 talks given in a row during this Thursday December 7 afternoon, in front of an audience of more than 210 HIV scientists, contained the same message: some of the major pharmaceutical companies are addressing the search of an HIV cure very seriously. We are over a period of time when their main goal was only selling life-long ART; there is now an overt race to find a cure.
Romas Geleziunas presentation was entitled “Quest for Virus Activators and Immune Modulators for HIV Eradication”. In the first part of his talk, the Gilead scientist described the in vitro system they have adapted from Bosque and Planelles (2009) for the screening of drugs capable of acting on HIV latency (figure 1). This test has been validated by using agents known to activate latent HIV, has a greater sensitivity than the original test, has been miniaturized (384-well plates) and automated.
He then presented data on HDAC inhibitors in the Gilead’s collection, in particular a compound named “GSI-002” which increased histone acetylation in vitro and in vivo without activating T cells, and is well tolerated in rats after a 2-3 weeks dosing: figures 2 & 3.
The screening of Gilead’s library also yielded other compounds with different modes of action like kinase inhibitors or Toll-like receptor 7 (TLR7) agonists. In particular “GS-9620” is a potent TLR7 agonist that has just moved to clinical trials in viral hepatitis (figure 4).
It remains to be determined if this kind of agent is able to enhance immunity to help eliminate HIV-infected cells (figure 5).
Roger Sutmuller talk was entitled “Drug Discovery for Latent HIV Reactivation”. The Janssen scientists first defined the ideal compound as able to:
-Reactivates latent HIV without overt T cell activation
-Show acceptable toxicity profile (no long term toxicity)
-Be combined with other HIV reactivating compounds (additive or synergistic effect on HIV reactivation)
By using HIV latency Jurkat cells, Janssen has already screened more than 35,000 compounds and selected some acting as HDAC inhibitors, others as PKC agonists and others with unknown modes of action (figure 6).
They have also developed their in-house primary T cell reactivation assay that helped confirm hits from Jurkat screens. They have also established a HIV latency mouse model and showed that proviral HIV DNA is recovered in successfully treated humanized mice (figure 7).
By using this model, they plan to study:
-HIV latent reservoir,
-HIV reactivating compounds,
-Viral RNA/DNA levels
-HIV rebound after treatment interruption.
In conclusion, pharmaceutical companies have now established:
-A panel of screen and confirmation tools available to identify latent HIV reactivating compounds;
-Robust primary T cell assay for latent HIV reactivation currently in use for screening dedicated compound sets and for testing hits coming from Jurkat screens
-Humanized mouse models.
The race towards an HIV cure has already started!
Key words: HDAC inhibitors, HIV Gilead, HIV Janssen, HIV cure, HIV cure research, HIV latency, HIV reservoirs