Discovery and Characterization of Latency-Reversing Compounds

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 DESCRIPTION (provided by applicant): The persistence of latent HIV in quiescent central memory T cells (Tcm) in individuals treated undergoing anti-retroviral therapy (ART) is well documented. It is this reservoir of virus that is thought to be the principal reason for the inabilty of current HIV treatment strategies to cure the infection. The possibility of reactivating latent HIV, and thus purging a person of latent HIV reservoirs, has prompted the search for HIV activating agents, but to date these efforts have not yielded tenable therapies. A clinical trial using a recombinant anti-CD3 antibody, and IL-2 to reactivate latent HIV was discontinued due to potent general T-cell activation and cytokine storm. Viral reactivation in the absence of global T cell activation is needed to avoid overproduction of inflammatory cytokines; not to mention the expansion of the latent HIV reservoir due to T cell proliferation. Plants are a rich source of molecules capable of modulating many human immunological responses, including activation of signaling pathways responsible for reactivation of latent HIV-1. We have identified 120 extracts from medicinal plants that are capable of reactivating latent HIV-1. Of these extracts, a significant proportion were found to spare T-cell activation and, therefore, constitute excellent candidates for viral eradication strategies. Based on these results, we conclude that the goal of identifying selective small molecule HIV activators with the desired qualities is possible. More importantly, exploration of these new latency reversing molecules will reveal mechanisms by which they can synergize with agents being explored in the clinic, and act to reactivate HIV in absence of general T cell activation. The mechanisms of action for these botanicals will be compared with the MOAs of known latency reversing agents for which signaling pathways resulting in transcriptional effects are characterized (such as protein kinase C and T-cell receptor agonists and others).