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

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

Volume: 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*

Affiliation:

• Laboratory of molecular virology, George Mason University, Discovery Hall Room 182, 10900 University Blvd., Manassas, VA 20110,United States

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

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.

Cite this article as:

Akpamagbo A. Yao , DeMarino Catherine, Pleet L. Michelle, Schwab Angela , Rodriguez Myosotys, Barclay A. Robert , Sampey Gavin , Iordanskiy Sergey , El-Hage Nazira and Kashanchi Fatah *, HIV-1 Transcription Inhibitors Increase the Synthesis of Viral Non-Coding RNA that Contribute to Latency, Current Pharmaceutical Design 2017; 23 (28) . https://dx.doi.org/10.2174/1381612823666170622101319