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Biology 2012, 1(1), 94-115; doi:10.3390/biology1010094
Review

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

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1,2
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1
 and
1,2,*
1 Department of Molecular Virology & Microbiology, Baylor College of Medicine, Houston, TX 77030, USA 2 Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
* Author to whom correspondence should be addressed.
Received: 15 May 2012 / Revised: 7 June 2012 / Accepted: 11 June 2012 / Published: 15 June 2012
(This article belongs to the Special Issue Structural and Molecular Biology of HIV)
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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 P-TEFb; HIV-1; Tat; T-loop phosphorylation; Cyclin T1; miRNA
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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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.

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