Controlling HIV latency by manipulating CycT1 turnover

Abstract Immune dysfunction associated with co-infection and AIDS-related cancers is commonly observed in HIV-infected individuals. In particular, gene expression programs in the immune system are often abnormally regulated in these individuals. We and other groups have recently discovered that the positive transcription factor b (P-TEFb), a critical cellular factor required for productive elongation of transcription, is severely down-regulated in quiescent and aberrant T cells. In resting CD4+ T cells, representing major latent HIV reservoirs, the expression of the cyclin T1 (CycT1) subunit of P-TEFb is diminished post-transcriptionally via currently unknown mechanisms, this being a main cause of HIV latency and tumor-specific T cells' defective response to check-point inhibitors and/or CAR-T cell therapies. Since increasing CycT1 is a prerequisite and mandatory step for optimal HIV reactivation and proper immune response against other pathogens and tumor cells, understanding the mechanism of CycT1 down-regulation is crucial. We have recently demonstrated that P-TEFb assembly regulated by phosphorylation determines the stability of CycT1. Also, we have identified all key players, including E3 ligases, involved in CycT1-degradation. Therefore, we hypothesize that increasing CycT1 proteins in resting and aberrant CD4+ T cells by manipulating cellular pathways to regulate P-TEFb assembly will reverse HIV latency and improve immune functions in HIV-infected individuals. In the proposed study, we will manipulate the cellular pathways regulating P-TEFb assembly and CycT1 stability to control HIV latency and improve immune functions. We will also identify previously uncharacterized "CycT1-degradation complexes", which will serve as new therapeutic targets. Successful completion of the proposed study will result in a new concept of T cell regulation modulated by the protein level of a master transcriptional regulator.