Dual Control of HIV Transcription Elongation: Virus-Specific Negative Control by NELF-E is Counterbalanced by Positive Transcription Factor P-TEFb
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Expression of the HIV provirus is regulated at the level of transcription by an intricate interplay between positive and negative factors. In the presence of positive transcription elongation factors such as the cellular cofactor Positive Transcription Elongation Factor b (PTEF-b), transcription proceeds efficiently, resulting in full-length HIV mRNA. Alternatively, paused elongation produces an accumulation of short, abortive transcripts. Non-processive transcription occurs in the presence of negative factors, such as Negative Elongation Factor (NELF), which has been shown to suppress elongation through direct interaction between its NELF-E subunit and the HIV TAR. This work is intended to ascertain whether these factors can potentially be manipulated to benefit treatment of HIV, either through therapeutics to target active, ongoing infection, or by manipulating the latent viral reservoir which currently prevents eradication of virus from the body.
This study used the development of dominant negative CycT1 mutants to attempt to specifically inhibit positive regulation of HIV transcription. Two separate CycT1 mutants were found to interfere with successful transcription of HIV mRNA by distinct mechanisms. One mutant forms a kinase-inactive complex with Tat, while the other causes specific degradation of Tat. On the opposing side of regulation, shRNA-expressing lentiviruses targeting NELF were applied to a re-activatable model of post-integration latency to better understand the associated transcriptional suppression. These results suggest the NELF-E subunit is essential for the suppression of transcription associated with latency, and that this NELF-E effect is specific to the Human Immunodeficiency Virus. These investigations demonstrate that the regulation of HIV transcription is a critical stage in the life cycle of the virus which can be exploited to not only gain a better understanding of the virus itself, but to possibly open new avenues for the future treatment of AIDS.
Document number: case1228234927
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=case1228234927
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