Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages.
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.
Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. ramakris@bcm.edu.
Rajesh
R
Ramakrishnan
Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. chiang@bcm.edu.
Karen
K
Chiang
Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. hliu@bcm.edu.
Hongbing
H
Liu
Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. budhiraj@bcm.edu.
Sona
S
Budhiraja
Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. hartdonahue@gmail.com.
Hart
H
Donahue
Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA. arice@bcm.edu.
Andrew P
AP
Rice