Abstract: Productive transcription of the integrated HIV-1 provirus is restricted by cellular factors that inhibit RNA polymerase II elongation. The viral Tat protein overcomes this by recruiting a general elongation factor, P-TEFb, to the TAR RNA element that forms at the 5’ end of nascent viral transcripts. P-TEFb exists in multiple complexes in cells, and its core consists of a kinase, Cdk9, and a regulatory subunit, either Cyclin T1 or Cyclin T2. Tat binds directly to Cyclin T1 and thereby targets the Cyclin T1/P-TEFb complex that phosphorylates the CTD of RNA polymerase II and the negative factors that inhibit elongation, resulting in efficient transcriptional elongation. P-TEFb is tightly regulated in cells infected by HIV-1—CD4+ T lymphocytes and monocytes/macrophages. A number of mechanisms have been identified that inhibit P-TEFb in resting CD4+ T lymphocytes and monocytes, including miRNAs that repress Cyclin T1 protein expression and dephosphorylation of residue Thr186 in the Cdk9 T-loop. These repressive mechanisms are overcome upon T cell activation and macrophage differentiation when the permissivity for HIV-1 replication is greatly increased. This review will summarize what is currently known about mechanisms that regulate P-TEFb and how this regulation impacts HIV-1 replication and latency.
Keywords: P-TEFb; HIV-1; Tat; T-loop phosphorylation; Cyclin T1; miRNA
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Ramakrishnan, R.; Chiang, K.; Liu, H.; Budhiraja, S.; Donahue, H.; Rice, A.P. Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages. Biology 2012, 1, 94-115.
Ramakrishnan R, Chiang K, Liu H, Budhiraja S, Donahue H, Rice AP. Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages. Biology. 2012; 1(1):94-115.
Ramakrishnan, Rajesh; Chiang, Karen; Liu, Hongbing; Budhiraja, Sona; Donahue, Hart; Rice, Andrew P. 2012. "Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages." Biology 1, no. 1: 94-115.