rvx-208 and HIV-Infections

Despite the advances in Human Immunodeficiency Virus (HIV) treatment, the cure for all HIV patients still poses a major challenge, which needs to be surpassed in the coming years. Among the strategies pursuing this aim, the 'kick-and-kill' approach, which involves the reactivation and elimination of a latent HIV reservoir that resides in some CD4

Topics: Anti-HIV Agents; CD4-Positive T-Lymphocytes; Histone Deacetylase Inhibitors; HIV Infections; HIV-1; Humans; Molecular Structure; Virus Latency

Persistent latent reservoir in resting CD4+ T cells is a major obstacle in curing HIV-1 infection. Effective strategies for eradication of the HIV-1 reservoir are urgently needed. We report here for the first time that two BET inhibitors, RVX-208, which has entered phase II clinical trials for diverse cardiovascular disorders, and PFI-1, which has been widely studied in oncology, can reactivate HIV-1 from latency. RVX-208 and PFI-1 treatment alone or in combination with other latency reversing agents efficiently reactivated HIV-1 transcription through an up-regulation of P-TEFb by increasing CDK9 Thr-186 phosphorylation in latently infected Jurkat T cells in vitro. The two BET inhibitors also reactivated HIV-1 transcription in cART treated patient-derived resting CD4+ T cells ex vivo, without influence on global immune cell activation. Our findings, in combination with previous reports, further confirm that BET inhibitors are a group of leading compounds for combating HIV-1 latency for viral eradication.

Topics: CD4 Antigens; CD4-Positive T-Lymphocytes; Cyclin-Dependent Kinase 9; HIV Infections; HIV-1; Humans; Jurkat Cells; Phosphorylation; Quinazolinones; Receptors, CCR5; tat Gene Products, Human Immunodeficiency Virus; Tumor Necrosis Factor-alpha; Virus Activation; Virus Latency