Negative Elongation Factor (NELF) Coordinates RNA Polymerase II Pausing, Premature Termination, and Chromatin Remodeling to Regulate HIV Transcription

• Published in: The Journal of biological chemistry Vol. 288; no. 36; pp. 25995 - 26003
• Main Authors: Natarajan, Malini, Schiralli Lester, Gillian M., Lee, Chanhyo, Missra, Anamika, Wasserman, Gregory A., Steffen, Martin, Gilmour, David.S., Henderson, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.09.2013; American Society for Biochemistry and Molecular Biology
• Subjects: CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Chromatin Assembly and Disassembly; Gene Regulation; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; HIV; HIV Infections - genetics; HIV Infections - metabolism; HIV-1 - physiology; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Jurkat Cells; Models, Biological; mRNA Cleavage and Polyadenylation Factors - genetics; mRNA Cleavage and Polyadenylation Factors - metabolism; Nuclear Receptor Co-Repressor 1 - genetics; Nuclear Receptor Co-Repressor 1 - metabolism; RNA Polymerase II; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Transcription Elongation Factors; Transcription Elongation, Genetic; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Regulation; Transcription Repressor; Transcription Termination, Genetic; Virus Latency - physiology; Transcription Regulation; Transcription Repressor; HIV; RNA Polymerase II; Transcription Elongation Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.496489

A barrier to eradicating HIV infection is targeting and eliminating latently infected cells. Events that contribute to HIV transcriptional latency include repressive chromatin structure, transcriptional interference, the inability of Tat to recruit positive transcription factor b, and poor processivity of RNA polymerase II (RNAP II). In this study, we investigated mechanisms by which negative elongation factor (NELF) establishes and maintains HIV latency. Negative elongation factor (NELF) induces RNAP II promoter proximal pausing and limits provirus expression in HIV-infected primary CD4+ T cells. Decreasing NELF expression overcomes RNAP II pausing to enhance HIV transcription elongation in infected primary T cells, demonstrating the importance of pausing in repressing HIV transcription. We also show that RNAP II pausing is coupled to premature transcription termination and chromatin remodeling. NELF interacts with Pcf11, a transcription termination factor, and diminishing Pcf11 in primary CD4+ T cells induces HIV transcription elongation. In addition, we identify NCoR1-GPS2-HDAC3 as a NELF-interacting corepressor complex that is associated with repressed HIV long terminal repeats. We propose a model in which NELF recruits Pcf11 and NCoR1-GPS2-HDAC3 to paused RNAP II, reinforcing repression of HIV transcription and establishing a critical checkpoint for HIV transcription and latency. Background: Multiple mechanisms contribute to HIV latency, including NELF-mediated RNA polymerase II (RNAP II) pausing. Results: Paused RNAP II recruits a transcription termination factor and a transcriptional corepressor complex to the HIV promoter. Conclusion: Paused RNAP II couples premature transcription termination and chromatin remodeling to maintain HIV latency. Significance: Paused RNAP II may be targeted to purge latent HIV infection.