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Front. Physiol. | doi: 10.3389/fphys.2018.01364

Dynamics of the gene regulatory network of HIV-1 and the role of viral non-coding RNAs on latency reversion

 Antonio Bensussen1, 2*, Christian Torres-Sosa3,  Ramón A. González2 and  José Díaz1, 2
  • 1Centro de Investigación en Dinámica Celular, Universidad Autónoma del Estado de Morelos, Mexico
  • 2Centro de Investigación en Dinámica Celular, Universidad Autónoma del Estado de Morelos, Mexico
  • 3Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico

The use of latency reversing agents (LRAs) is currently a promising approach to eliminate latent reservoirs of HIV-1. However, this strategy has not been successful in vivo. It has been proposed that cellular post-transcriptional mechanisms are implicated in the underperformance of LRAs, but it is not clear whether proviral regulatory elements like viral non-coding RNAs (vncRNAs) are also implicated. In order to visualize the complexity of the HIV-1 gene expression, we used experimental data to construct a gene regulatory network (GRN) of latent proviruses in resting CD4+ T cells. We then analyzed the dynamics of this GRN using Boolean and continuous mathematical models. Our simulations predict that vncRNAs are able to counteract the activity of LRAs, which may explain the failure of these compounds to reactivate latent reservoirs of HIV-1. Moreover, our results also predict that using inhibitors of histone methyltransferases, such as chaetocin, together with releasers of the positive transcription elongation factor (P-TEFb), like JQ1, may increase proviral reactivation despite self-repressive effects of vncRNAs.

Keywords: HIV-1, Viral non-coding RNAs, reservoirs, antiretroviral therapy, LRAs, dynamics, Boolean Networks.

Received: 29 Mar 2018; Accepted: 07 Sep 2018.

Edited by:

Matteo Barberis, University of Amsterdam, Netherlands

Reviewed by:

Dimiter Prodanov, Interuniversity Microelectronics Centre (IMEC), Belgium
Pengyue Zhang, Indiana University Bloomington, United States  

Copyright: © 2018 Bensussen, Torres-Sosa, González and Díaz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: PhD. Antonio Bensussen, Universidad Autónoma del Estado de Morelos, Centro de Investigación en Dinámica Celular, Av. Universidad No. 1001, Col Chamilpa, Cuernavaca, 62209, Morelos, Mexico,