Developmental Potential of IN-TACKs

About This Grant

PROJECT SUMMARY/ABSTRACT HIV-1 infection remains a global health crisis. While highly active antiretroviral therapy (ART) allows most people to live with HIV, ART is not curative. HIV-1 exists within a reservoir of latently-infected cells as an integrated provirus DNA that is rekindled for virus gene expression and viral recrudescence upon ART cessation. The field of HIV Cure is accordingly constantly developing new ways, on the one hand, to permanently silence HIV-1 gene expression (block and lock), or, on the other hand, to enhance gene expression and then to eliminate HIV+ cells from the body (shock and kill). HIV-1 structural proteins and replication enzymes are expressed from proviral DNA as Gag and Gag-Pol polyprotein precursors, respectively, which are cleaved into constitutive components by the viral protease (PR) enzyme during virus assembly and maturation. Retroviral PRs are quasi site specific enzymes, and retroviruses have accordingly evolved to regulate PR activity to limit the extent of cellular proteolysis, which otherwise could be leveraged to detect the virus as a foreign invader. Indeed, the field has in recent years described effective small molecule kill modulators, called RT-TACKs, because they work by engaging the reverse transcriptase (RT) domain within Gag-Pol to effect premature Gag-Pol dimerization, which in turn prematurely activates the viral PR to cleave cellular inflammasome modulators and elicit pyroptotic cell death. In addition to protease and RT, the integrase domain encompasses part (the C-terminal portion) of Gag- Pol. Integrase has previously been implicated in regulating PR activity during HIV-1 maturation, but the underlying molecular mechanisms have remained unclear. In this study, we have assessed if integrase-targeting compounds might also elicit pyroptotic cell death. The work described in this application will determine the developmental potential of integrase-targeted activator of cell kill (IN-TACK) compounds for elimination of HIV+ cells.