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HIV-1 Transcription Inhibitors Increase the Synthesis of Viral Non-Coding RNA that Contribute to Latency

[ Vol. 23 , Issue. 28 ]

Author(s):

Yao A. Akpamagbo, Catherine DeMarino, Michelle L. Pleet, Angela Schwab, Myosotys Rodriguez, Robert A. Barclay, Gavin Sampey, Sergey Iordanskiy, Nazira El-Hage and Fatah Kashanchi*   Pages 4133 - 4144 ( 12 )

Abstract:


Background: HIV-1 can be preserved in long-lived resting CD4+ T- and myeloid cells, forming a viral reservoir in tissues of the infected individuals. Infected patients primarily receive cART, which, to date, is the most efficient treatment against HIV/AIDS. However, the major problem in the eradication of HIV-1 from patients is the lack of therapeutic approaches to recognize the latent HIV-1 provirus and to eliminate latently infected cells.

Results: In the current review, we describe the effect of HIV-1 transcriptional inhibitors CR8#13 and F07#13 using a series of in vitro and in vivo assays. We found that both of these compounds regulate p-TEFb in infected cells, and terminate transcription at two sites, either at the LTR or early gag regions. The resulting short transcripts are termed TAR and TAR-gag, respectively. These nascent RNAs are capable of binding to SWI/SNF components, including mSin3A/HDAC-1 complex and potentially serve as a scaffolding RNA. Both TAR and TAR-gag are detected as large complexes from treated infected cells when using chromatography. Both transcripts are non-coding in T-cells and monocytes, and potentially recruit suppressive factors along with RNAbinding proteins to the DNA resulting in Transcriptional Gene Silencing (TGS). Finally, these compounds suppress activated virus when using a latent humanized mouse model.

Conclusion: Collectively, these data implicate transcription inhibitors as regulators of the viral promoter through short non-coding RNAs and chromatin remodeling factors. These RNAs give specificity toward either viral DNA and/or nascent mRNA when functioning as TGS.

Keywords:

HIV-1, Transcription, non-coding RNA, TAR, latency, CRC.

Affiliation:

Laboratory of Molecular Virology, George Mason University, Manassas, Virginia, Laboratory of Molecular Virology, George Mason University, Manassas, Virginia, Laboratory of Molecular Virology, George Mason University, Manassas, Virginia, Laboratory of Molecular Virology, George Mason University, Manassas, Virginia, Department of Immunology, Florida International University, Miami, FL, Laboratory of Molecular Virology, George Mason University, Manassas, Virginia, Laboratory of Molecular Virology, George Mason University, Manassas, Virginia, Laboratory of Molecular Virology, George Mason University, Manassas, Virginia, Department of Immunology, Florida International University, Miami, FL, Laboratory of molecular virology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110



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