HIV latency is a widely accepted health problem because the drugs that curb viral replication (anti-retroviral therapy, ART) do not eradicate the virus from the infected individual. Therefore, novel therapeutic strategies to attack the latently infected reservoirs and prevent a rebound of virus after withdrawal of ART are urgently needed. Over the past decade, great progress has been made in identifying several small molecules that can reactivate latent HIV without activating CD4+ T cells in several in vitro cell-based or in ex vivo models. However, these compounds do not reverse HIV latency in vivo. This poses a great barrier for the eradication of HIV and suggests that studies in cell-based models must be validated using primary T cells from aviremic patients under suppressive therapy. Using a high-throughput screening for small compounds capable of reactivating silenced viral loci, we have recently identified a novel and unique set of 70 lead compounds with latency-reactivating potential that we named SMORE for Small MOlecule REactivators. This research project aims at further characterizing these small compounds for their potency, efficacy, cell toxicity and basic mechanism of action using both cell-based models and ex vivo approaches with primary T cells from aviremic patients obtained from the HIV Clinics at the U.T. Southwestern Medical Center campus. This study will lead us not only to a better basic understanding of the molecular underpinnings of latency but will also elucidate novel latency-reactivating agents and creative combinatorial strategies for HIV eradication in patients. The work proposed builds on a recent publication and a novel set of preliminary data that identified SMORE as novel candidates to purge latent HIV reservoirs. Given that SMORE reactivate proviral transcription, they emerge as key candidates for rational HIV eradication strategies in HIV infected patients. The project will be conducted at U.T. Southwestern Medical Center, which has state-of-the-art technologies and a very rich atmosphere of collaborators in complementary fields such as pharmacology and immunology. Collectively, these discoveries will expand our spectrum of therapeutic approaches and combinatorial strategies to target HIV latency in our race towards a functional cure.
This project will combine a wide-range of approaches to characterize a novel set of lead compounds identified on a recent high-throughput screening with HIV latency-reversing potential using cell-based models and primary cells from aviremic HIV patients. We aim to precisely identify compounds with high potency and efficacy, low general cell toxicity and selectivity for HIV over cellular genes. These compounds will be useful not only to reactivate latent HIV pools but also to selectively sensitize these infected cells to therapeutic agents. Thus, the knowledge generated from this study will aid in the design of unique therapeutics to eradicate latent HIV in efforts towards a functional cure.
| Bacon, Curtis W; D'Orso, Iván (2018) CDK9: a signaling hub for transcriptional control. Transcription :1-19 |
