Replication of HIV-1 is critically dependent on the viral transactivator protein known as Tat. Tat function is mediated by a cellular protein kinase complex termed TAK/P-TEFb. This kinase is composed of Cdk9 as the catalytic subunit, and cyclin T1 as a regulatory subunit that makes direct protein-protein contact with Tat. Given its essential role in HIV-1 replication, regulation of TAK/P-TEFb function in cells relevant to HIV-1 infection is potentially an important research topic. Recent work has shown that cyclin T1 protein levels are transiently induced during macrophage differentiation. In monocytes freshly isolated from healthy blood donors, cyclin T1 protein levels are low and are strongly induced during the first few days of differentiation to macrophages. Remarkably, after about one week of differentiation, cyclin T1 levels decline to very low levels. In contrast, Cdk9 protein levels are high in freshly isolated monocytes and remain high during differentiation. In agreement with the transient induction of cyclin T1, TAK/P-TEFb kinase activity and Tat transactivation function are high early, but low to absent late, during macrophage differentiation. These changes in cyclin T1 protein levels are regulated by a post-transcriptional mechanism(s). Additionally, lipopolysaccharide, a component of the cell wall of Gram negative bacteria, induces cyclin T1 after it has declined late in macrophage differentiation. Thus, HIV-infected macrophages may serve as a latent viral reservoir due to the absence of cyclin T1 protein. Furthermore, cyclin T1 induction by bacterial infections or other signals may be involved in reactivation of latent viruses. Work is proposed in this application to investigate molecular mechanisms that regulate cyclin T1 expression in macrophages, as well as to investigate signals and signal transduction pathways involved in this regulation. Work is also proposed to investigate how regulation of cyclin T1 expression in macrophages influences HIV-1 replication. Completion of the proposed research may provide novel targets for drug development. ? ?
| Rice, Andrew P (2009) Dysregulation of positive transcription elongation factor B and myocardial hypertrophy. Circ Res 104:1327-9 |
| Sung, Tzu-Ling; Rice, Andrew P (2009) miR-198 inhibits HIV-1 gene expression and replication in monocytes and its mechanism of action appears to involve repression of cyclin T1. PLoS Pathog 5:e1000263 |
