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      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

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          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 (T CM), full-length virus infection (HIV NL4-3) 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.

          Author Summary

          The major hindrance to an HIV cure is the ability of the virus to persist in a latent state despite antiretroviral therapy. It is difficult to study this latent state in the HIV-infected patient because only a small proportion of cells in the body are affected and current technologies are not able to identify these cells. Therefore, models in the laboratory have been developed to study HIV latency. However, these models have not been adequately characterized with the latest genomic technologies. We have characterized our model of HIV latency using global gene expression analysis (i.e., RNA-Seq). Our model aims to reflect HIV latency in patients by using primary central memory CD4 T cells, wild type virus, and antiretroviral therapy. Our main finding was that signaling through the p53 protein characterized the latent state, and may be important in its establishment. This has implications for a better understanding of HIV latency which may lead to new therapies. In a broader context, we validated the latent state of our model of HIV latency, which can now be used with confidence to evaluate compounds used in strategies to cure HIV, search for markers of HIV latency, and further investigate the mechanisms leading to the establishment of latency.

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          Most cited references60

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          Entrez Gene: gene-centered information at NCBI

          Entrez Gene (www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene) is NCBI's database for gene-specific information. It does not include all known or predicted genes; instead Entrez Gene focuses on the genomes that have been completely sequenced, that have an active research community to contribute gene-specific information, or that are scheduled for intense sequence analysis. The content of Entrez Gene represents the result of curation and automated integration of data from NCBI's Reference Sequence project (RefSeq), from collaborating model organism databases, and from many other databases available from NCBI. Records are assigned unique, stable and tracked integers as identifiers. The content (nomenclature, map location, gene products and their attributes, markers, phenotypes, and links to citations, sequences, variation details, maps, expression, homologs, protein domains and external databases) is updated as new information becomes available. Entrez Gene is a step forward from NCBI's LocusLink, with both a major increase in taxonomic scope and improved access through the many tools associated with NCBI Entrez.
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            PUMA, a novel proapoptotic gene, is induced by p53.

            The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named PUMA (p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain-containing proteins (PUMA-alpha and PUMA-beta) that are induced in cells following p53 activation. PUMA-alpha and PUMA-beta show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of PUMA expression reduced the apoptotic response to p53, and PUMA is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway.
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              The Integrated Genome Browser: free software for distribution and exploration of genome-scale datasets

              Summary: Experimental techniques that survey an entire genome demand flexible, highly interactive visualization tools that can display new data alongside foundation datasets, such as reference gene annotations. The Integrated Genome Browser (IGB) aims to meet this need. IGB is an open source, desktop graphical display tool implemented in Java that supports real-time zooming and panning through a genome; layout of genomic features and datasets in moveable, adjustable tiers; incremental or genome-scale data loading from remote web servers or local files; and dynamic manipulation of quantitative data via genome graphs. Availability: The application and source code are available from http://igb.bioviz.org and http://genoviz.sourceforge.net. Contact: aloraine@uncc.edu
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                29 November 2016
                November 2016
                : 12
                : 11
                : e1006026
                Affiliations
                [1 ]Graduate Program in Bioinformatics and Systems Biology, University of California San Diego, La Jolla, California, United States of America
                [2 ]San Diego VA medical Center and Veterans Medical Research Foundation, San Diego, California, United States of America
                [3 ]Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, Hampshire, United Kingdom
                [4 ]Department of Medicine, University of California San Diego, La Jolla, California, United States of America
                [5 ]Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
                [6 ]Department of Pathology, University of California San Diego, La Jolla, California, United States of America
                [7 ]UNC HIV Cure Center, Department of Medicine, Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
                Emory University, UNITED STATES
                Author notes

                DDR has consulted for Chimerix, Gilead, Antiva, Monogram and the HIV Immunotherapeutics Institute. All other authors have declared that no competing interests exist.

                • Conceptualization: CHWh BM NBB LJM CAS DMM DDR VP AB CHWo.

                • Data curation: CHWh BM AB CHWo.

                • Formal analysis: CHWh BM AB CHWo.

                • Funding acquisition: CAS DMM DDR VP AB CHWo.

                • Investigation: CHWh BM AB CHWo.

                • Methodology: CHWh BM NBB AB CHWo.

                • Project administration: AB CHWo.

                • Resources: CAS DMM DDR VP AB CHWo.

                • Software: CHWh BM CHWo.

                • Supervision: AB CHWo.

                • Validation: CHWh BM NBB AB CHWo.

                • Visualization: CHWh BM AB CHWo.

                • Writing – original draft: CHWh AB CHWo.

                • Writing – review & editing: CHWh BM NBB LJM CAS DMM DDR VP AB CHWo.

                [¤]

                Current address: Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, George Washington University, Washington DC, United States of America

                ‡ These senior authors contributed equally to the manuscript.

                Author information
                http://orcid.org/0000-0002-7211-9751
                http://orcid.org/0000-0001-5714-0002
                http://orcid.org/0000-0002-8800-2160
                Article
                PPATHOGENS-D-16-01341
                10.1371/journal.ppat.1006026
                5127598
                27898737
                f7d6044a-f939-4c91-b7b0-3ab034d87df1
                © 2016 White et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 June 2016
                : 26 October 2016
                Page count
                Figures: 7, Tables: 1, Pages: 23
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI096113
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI096113
                Award Recipient : Douglas R Richman
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI096113
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI096113
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI096113
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: P30 AI36214
                Award Recipient : Douglas R Richman
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: OPP1045955
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009012, Veterans Affairs San Diego Healthcare System;
                Award ID: BX001160
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI080193
                Award Recipient : Douglas R Richman
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: AI104282
                Award Recipient :
                Funded by: Veterans Affairs Office of Research and Development
                Award ID: BX007080
                Award Recipient : Cory Haley White
                Funded by: funder-id http://dx.doi.org/10.13039/100007496, Biomedical Laboratory Research and Development, VA Office of Research and Development;
                Award ID: BX007080
                Award Recipient :
                This work was performed with the support of the Collaboratory of AIDS Researchers for Eradication (CARE), a Martin Delaney Collaboratory funded through a National Institutes of Health grant (AI096113) to DMM, DDR, VP, CAS and CHWo; by the UCSD Center for AIDS Research from the National Institutes of Health to DDR (P30 AI36214); by a grant from the Bill & Melinda Gates Foundation through the Grand Challenges Explorations initiative to AB (OPP1045955); and a Veterans Affairs grants (BX001160 and BX007080) to CAS and NBB, respectively; as well as other National Institutes of Health grants to DRR (AI080193) and to CHWo (AI104282). The views expressed here are those of the authors and do not necessarily reflect the position or policy of the Veterans Affairs or the United States government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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                Custom metadata
                This manuscript contains analysis of RNA-Seq data available through the Gene Expression Omnibus (GEO) accession number GSE81810. All other relevant data are within the paper and its Supporting Information files.

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