In-Vitro Subtype-Specific Modulation of HIV-1 Trans-Activator of Transcription (Tat) on RNAi Silencing Suppressor Activity and Cell Death

Ronsard, Larance; S. Yousif, Ashraf; Ramesh, Janani; Sumi, N.; Gorman, Matthew; G. Ramachandran, Vishnampettai; C. Banerjea, Akhil

Human immunodeficiency virus (HIV) is a global health concern affecting millions of individuals with a wide variety of currently circulating subtypes affecting various regions of the globe. HIV relies on multiple regulatory proteins to modify the host cell to promote replication in infected T cells, and these regulatory proteins can have subtle phenotypic differences between subtypes. One of these proteins, HIV-1 Trans-Activator of Transcription (Tat), is capable of RNA interference (RNAi) Silencing Suppressor (RSS) activity and induction of cell death in T cells. However, the subtype-specific RSS activity and induction of cell death have not been explored. We investigated the ability of Tat subtypes and variants to induce RSS activity and cell death. TatB, from HIV-1 subtype B, was found to be a potent RSS activator by 40% whereas TatC, from HIV-1 subtype C, showed 15% RSS activity while subtype TatC variants exhibited varying levels. A high level of cell death (50–53%) was induced by subtype TatB when compared to subtype TatC (25–28%) and varying levels were observed with subtype TatC variants. These differential activities could be due to variations in the functional domains of Tat. These observations further our understanding of subtype-specific augmentation of Tat in HIV-1 replication and pathogenesis.