Mentor: Wendy Maury, Ph.D.
Lab Phone: 335-7612

The Role of PTEF-b in HIV Replication

HIV, the causative agent in AIDS, is a growing concern in the world today as 42 million people are infected with the deadly virus. During viral infection HIV uses the cellular transcription control machinery to regulate its own transcription. It was recently discovered that P-TEFb, a cellular cyclin and cyclin dependent kinase complex that controls the elongation phase of transcription by RNA polymerase II in cells, is required for HIV Tat transactivation. Tat, a virally encoded, transcriptional activator that is needed for viral infectivity, recruits cellular P-TEFb to the site of HIV mRNA elongation stimulating the production of full-length HIV transcripts. P-TEFb is then capable of phosphorylating the carboxyl termini domain (CTD) of the cellular RNA polymerase II (polII) and by doing so it allows the polymerase to overcome negative elongation factors. This phosphorylation event results in the transition from abortive to productive elongation of viral transcripts. Interestingly, while P-TEFb is required for the expression of most if not all cellular genes, HIV transcription exhibits enhanced sensitivity to P-TEFb inhibitors suggesting that HIV transcription has a greater dependence on P-TEFb activity than cellular genes. The reason for this difference in sensitivity between cellular genes and Tat-dependant viral transcription and replication is not understood. A form of P-TEFb that contains a small cellular RNA termed 7SK that is capable of dissociating from P-TEFb has been recently described. The dissociation of 7SK from the complex has been shown to correlate with an increase in cellular P-TEFb activity. Our preliminary data shows that low concentrations of P-TEFb inhibitors that are capable of inhibiting HIV replication in tissue culture also dissociate 7SK from P-TEFb but have little or no effect on transcription of cellular genes. These observations have led us to hypothesize that in the presence of Tat the HIV promoter requires or preferentially uses the large form of P-TEFb; the small form that appears to be utilized by cellular genes may not (or perhaps cannot) be utilized by HIV to promote elongation. Since small quantities of P-TEFb inhibitors are capable of blocking HIV replication without affecting cellular transcription or cell growth then research on the role of P-TEFb in HIV transcription and replication may prove significant for the development of new anti-viral therapies.

Biglione S, Byers SA, Price JP, Nguyen VT, Bensaude O, Price DH, Maury W. Inhibition of HIV-1 replication by P-TEFb inhibitors DRB, seliciclib and flavopiridol correlates with release of free P-TEFb from the large, inactive form of the complex. Retrovirology. 2007 Jul 11;4:47. PubMed PMID: 17625008; PubMed Central PMCID: PMC1948018.

Sedore SC, Byers SA, Biglione S, Price JP, Maury WJ, Price DH. Manipulation of P-TEFb control machinery by HIV: recruitment of P-TEFb from the large form by Tat and binding of HEXIM1 to TAR. Nucleic Acids Res. 2007;35(13):4347-58. Epub 2007 Jun 18. PubMed PMID: 17576689; PubMed Central PMCID: PMC1935001.