Constitutively-active Positive Transcription Factor b (P-TEFb) prevents viral latency.

Abstract

While many cellular and viral mechanisms are associated with proviral latency, the positive transcription factor b (P-TEFb), a cellular co-factor of the nuclear factor kappa B and viral transactiator proteins, plays a critical role in low viral transcription levels in resting infected cells. P-TEFb, comprised of CDK9 and Cyclin T1 (CycT1), is absent in quiescent CD4+T cells that represent the bulk of the viral latent reservoir. In these cells, the CycT1 subunit is dephosphorylated and dissociated from CDK9, leading to its rapid proteasomal degradation. Based on the knowledge of CycT1 phosphorylation and proteolysis, we designed a mutant CycT1 protein [constitutively active (CA)-CycT1] that is resistant to protein degradation and is stably expressed in resting CD4+ T cells. Interestingly, the expression of CA-CycT1 significantly delayed the establishment of viral latency in CD4+ T cells. This is the first example of expressing a high level of CycT1 proteins in resting CD4+ T cells, which modulates viral latency and T cell functions. This finding presents a significant therapeutic potential for the development of effective therapies for latent viral infections.