Reactivation of latent HIV in vivo for the purpose of purging the viral reservoir has become a formidable challenge. One major problem is to find stimuli that will effectively reactivate the virus without causing overt T-cell activation and proliferation.To address this problem, we have performed a medium-throughput screen of chemical and natural product libraries. This work describes the discovery, the properties and the chemical structures of a family of compounds (hereby referred to as �C7�) that was found through this screen.Incubation latently infected TCM cells with C7 led to viral reactivation levels that were about 70-80% of those obtained with control anti-CD3/CD28 stimulation. The activation profile of the C7-treated cells was indistinguishable from that of untreated, resting cells as evidenced by a lack of induction of CD25 and CD69. C7 also failed to induce cellular proliferation in the range of concentrations tested. C7 activates latent HIV through sustained phosphorylation of STAT5, which contrasts with the transient phosphorylation of STAT5 that is observed with gamma-c cytokine stimulation. C7 induced reactivation from latency can be blocked by JAK and STAT5 inhibitors.Surprisingly, stimulation of cells with C7 reactivated latent HIV without inducing a concomitant increase in cyclin T levels or CDK9 phosphorylation. When tested in the virus outgrowth assay that uses aviremic patient cells, C7 was able to reactivate latent viruses.These results demonstrate that a JAK/STAT-mediated signaling pathway can beutilized to trigger activation of latent proviruses in primary cells in vitro. Key signaling elements controlling this pathway should be considered as novel targets. The C7 compound and related molecules targeting this pathway belong to a chemical family not previously used as pharmacological agents.

New family of compounds that reactivate latent HIV in central memory T cells

248th National Meeting (2014)

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