The University of Southampton
University of Southampton Institutional Repository

Transcriptomic analysis implicates the p53 signaling pathway in the establishment of HIV-1 latency in central memory CD4 T Cells in an in vitro model

Transcriptomic analysis implicates the p53 signaling pathway in the establishment of HIV-1 latency in central memory CD4 T Cells in an in vitro model
Transcriptomic analysis implicates the p53 signaling pathway in the establishment of HIV-1 latency in central memory CD4 T Cells in an in vitro model

The search for an HIV-1 cure has been greatly hindered by the presence of a viral reservoir that persists despite antiretroviral therapy (ART). Studies of HIV-1 latency in vivo are also complicated by the low proportion of latently infected cells in HIV-1 infected individuals. A number of models of HIV-1 latency have been developed to examine the signaling pathways and viral determinants of latency and reactivation. A primary cell model of HIV-1 latency, which incorporates the generation of primary central memory CD4 T cells (TCM), full-length virus infection (HIVNL4-3) and ART to suppress virus replication, was used to investigate the establishment of HIV latency using RNA-Seq. Initially, an investigation of host and viral gene expression in the resting and activated states of this model indicated that the resting condition was reflective of a latent state. Then, a comparison of the host transcriptome between the uninfected and latently infected conditions of this model identified 826 differentially expressed genes, many of which were related to p53 signaling. Inhibition of the transcriptional activity of p53 by pifithrin-α during HIV-1 infection reduced the ability of HIV-1 to be reactivated from its latent state by an unknown mechanism. In conclusion, this model may be used to screen latency reversing agents utilized in shock and kill approaches to cure HIV, to search for cellular markers of latency, and to understand the mechanisms by which HIV-1 establishes latency.

Journal Article
1553-7366
White, Cory H.
45233a78-f0c9-4696-8aaf-1b2673f83c91
Moesker, Bastiaan
4d8a2308-e949-4c0d-8ad5-6099b5c8aa09
Beliakova-Bethell, Nadejda
72698b03-9c79-4ae8-89a8-2c64fe30e11e
Martins, Laura J.
0d79a85d-bd64-46a8-9b7c-2ef5c6b664ec
Spina, Celsa A.
c8449eb5-acfe-4ecf-b09f-838687908459
Margolis, David M.
20b39c84-66a1-4033-ac58-c14e57619d7e
Richman, Douglas D.
978207ff-1609-4247-96c6-b269b743ea14
Planelles, Vicente
7bc12a92-79d4-43d7-aae3-45db51c93bfe
Bosque, Alberto
150e32be-c057-43a5-9d81-3f28b88796df
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d
White, Cory H.
45233a78-f0c9-4696-8aaf-1b2673f83c91
Moesker, Bastiaan
4d8a2308-e949-4c0d-8ad5-6099b5c8aa09
Beliakova-Bethell, Nadejda
72698b03-9c79-4ae8-89a8-2c64fe30e11e
Martins, Laura J.
0d79a85d-bd64-46a8-9b7c-2ef5c6b664ec
Spina, Celsa A.
c8449eb5-acfe-4ecf-b09f-838687908459
Margolis, David M.
20b39c84-66a1-4033-ac58-c14e57619d7e
Richman, Douglas D.
978207ff-1609-4247-96c6-b269b743ea14
Planelles, Vicente
7bc12a92-79d4-43d7-aae3-45db51c93bfe
Bosque, Alberto
150e32be-c057-43a5-9d81-3f28b88796df
Woelk, Christopher H.
4d3af0fd-658f-4626-b3b5-49a6192bcf7d

White, Cory H., Moesker, Bastiaan, Beliakova-Bethell, Nadejda, Martins, Laura J., Spina, Celsa A., Margolis, David M., Richman, Douglas D., Planelles, Vicente, Bosque, Alberto and Woelk, Christopher H. (2016) Transcriptomic analysis implicates the p53 signaling pathway in the establishment of HIV-1 latency in central memory CD4 T Cells in an in vitro model. PLoS Pathogens, 12 (11). (doi:10.1371/journal.ppat.1006026).

Record type: Article

Abstract

The search for an HIV-1 cure has been greatly hindered by the presence of a viral reservoir that persists despite antiretroviral therapy (ART). Studies of HIV-1 latency in vivo are also complicated by the low proportion of latently infected cells in HIV-1 infected individuals. A number of models of HIV-1 latency have been developed to examine the signaling pathways and viral determinants of latency and reactivation. A primary cell model of HIV-1 latency, which incorporates the generation of primary central memory CD4 T cells (TCM), full-length virus infection (HIVNL4-3) and ART to suppress virus replication, was used to investigate the establishment of HIV latency using RNA-Seq. Initially, an investigation of host and viral gene expression in the resting and activated states of this model indicated that the resting condition was reflective of a latent state. Then, a comparison of the host transcriptome between the uninfected and latently infected conditions of this model identified 826 differentially expressed genes, many of which were related to p53 signaling. Inhibition of the transcriptional activity of p53 by pifithrin-α during HIV-1 infection reduced the ability of HIV-1 to be reactivated from its latent state by an unknown mechanism. In conclusion, this model may be used to screen latency reversing agents utilized in shock and kill approaches to cure HIV, to search for cellular markers of latency, and to understand the mechanisms by which HIV-1 establishes latency.

Text
journal.ppat.1006026 - Version of Record
Available under License Creative Commons Attribution.
Download (3MB)

More information

Accepted/In Press date: 26 October 2016
e-pub ahead of print date: 29 November 2016
Keywords: Journal Article
Organisations: Human Development & Health, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 407170
URI: https://eprints.soton.ac.uk/id/eprint/407170
ISSN: 1553-7366
PURE UUID: a150ceca-4c25-4012-857a-7f2825e65a13

Catalogue record

Date deposited: 31 Mar 2017 01:04
Last modified: 02 Dec 2019 19:17

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×