Making a Short Story Long: Regulation of P-TEFb and HIV-1 Transcriptional Elongation in CD4+ T Lymphocytes and Macrophages

Biology

Rajesh Ramakrishnan¹  Karen Chiang¹  Hongbing Liu¹  Sona Budhiraja¹  Hart Donahue¹ 

[1] Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA;

关键词: P-TEFb;    HIV-1;    Tat;    T-loop phosphorylation;    Cyclin T1;    miRNA;   

DOI  :  10.3390/biology1010094

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.