| The latent reservoir for HIV-1 in resting CD4+ T cells remains a major barrier to HIV-1 eradication, even though highly active antiretroviral therapy (HAART) can successfully reduce plasma HIV-1 levels in adherent patients to below the detection limit of clinical assays and reverse disease progression. The absence of viral gene expression in latently infected cells allows evasion from immune surveillance as well as HAART, which only targets replicating viruses. However, following cellular activation, these latent HIV-1 genomes can be transcribed, and viruses will be produced, leading to quick rebound of viremia upon the discontinuation of HAART.;Elimination of this latent reservoir is critical to curing HIV-1 infection. Eradication strategies involve reactivation of this latent reservoir; However, agents that reactivate latent HIV-1 through nonspecific T cell activation are toxic. In order to explore potential therapeutically candidates that reverse HIV-1 latency without inducing global T cell activation, we screened a total of more than 10,000 small molecules using the latently infected bcl-2 -transduced primary CD4+ T cell model.;From the screening results and follow-up studies, we demonstrated that the FDA-approved drug disulfiram reactivates latent HIV-1 in our primary cell model without inducing global T cell activation. To further assess its clinical potential in reducing the latent reservoir, a clinical trial in patients on HAART is currently being carried out. In addition, based on the structures of several initial hits, and analysis on the structure-activity relationships, we identified two classes of structural related quinolin-8-ol derivatives that are active in reversing HIV-1 latency while do not cause the release of inflammatory cytokines. These compounds have lead-like pharmacological properties, as well as the potential for further chemical modifications to improve activity and reduce toxicity while retaining drug-like characteristics.;In conclusion, we discovered novel agents that can induce latent HIV-1 in a primary cell model without causing a substantial degree of T cell activation. This work expands the number of known latency-reversing agents and provides new scaffolds for drug development research. Although it is not yet clear whether disulfiram or the quinolin-8-ol analogs can reactivate latent HIV-1 in vivo, it is possible that these compounds, or their derivatives, may be useful in future eradication strategies, either alone or in combination with other treatments. |
