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      A mature macrophage is a principal HIV-1 cellular reservoir in humanized mice after treatment with long acting antiretroviral therapy

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          Abstract

          Background

          Despite improved clinical outcomes seen following antiretroviral therapy (ART), resting CD4+ T cells continue to harbor latent human immunodeficiency virus type one (HIV-1). However, such cells are not likely the solitary viral reservoir and as such defining where and how others harbor virus is imperative for eradication measures. To such ends, we used HIV-1 ADA-infected NOD.Cg- Prkdc scid Il2rg tm1Wjl /SzJ mice reconstituted with a human immune system to explore two long-acting ART regimens investigating their abilities to affect viral cell infection and latency. At 6 weeks of infection animals were divided into four groups. One received long-acting (LA) cabotegravir (CAB) and rilpivirine (RVP) (2ART), a second received LA CAB, lamivudine, abacavir and RVP (4ART), a third were left untreated and a fourth served as an uninfected control. After 4 weeks of LA ART treatment, blood, spleen and bone marrow (BM) cells were collected then phenotypically characterized. CD4+ T cell subsets, macrophages and hematopoietic progenitor cells were analyzed for HIV-1 nucleic acids by droplet digital PCR.

          Results

          Plasma viral loads were reduced by two log 10 or to undetectable levels in the 2 and 4ART regimens, respectively. Numbers and distributions of CD4+ memory and regulatory T cells, macrophages and hematopoietic progenitor cells were significantly altered by HIV-1 infection and by both ART regimens. ART reduced viral DNA and RNA in all cell and tissue compartments. While memory cells were the dominant T cell reservoir, integrated HIV-1 DNA was also detected in the BM and spleen macrophages in both regimen-treated mice.

          Conclusion

          Despite vigorous ART regimens, HIV-1 DNA and RNA were easily detected in mature macrophages supporting their potential role as an infectious viral reservoir.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12977-017-0344-7) contains supplementary material, which is available to authorized users.

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          Most cited references65

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          Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy.

          The hypothesis that quiescent CD4+ T lymphocytes carrying proviral DNA provide a reservoir for human immunodeficiency virus-type 1 (HIV-1) in patients on highly active antiretroviral therapy (HAART) was examined. In a study of 22 patients successfully treated with HAART for up to 30 months, replication-competent virus was routinely recovered from resting CD4+ T lymphocytes. The frequency of resting CD4+ T cells harboring latent HIV-1 was low, 0.2 to 16.4 per 10(6) cells, and, in cross-sectional analysis, did not decrease with increasing time on therapy. The recovered viruses generally did not show mutations associated with resistance to the relevant antiretroviral drugs. This reservoir of nonevolving latent virus in resting CD4+ T cells should be considered in deciding whether to terminate treatment in patients who respond to HAART.
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            Tissue biology perspective on macrophages.

            Macrophages are essential components of mammalian tissues. Although historically known mainly for their function in host defense and the clearance of apoptotic cells, macrophages are now increasingly recognized as serving many roles in tissue development, homeostasis and repair. In addition, tissue-resident macrophages have many tissue-specific functional characteristics, which are a reflection of distinct gene-expression programs. Here we discuss the emerging views of macrophage biology from evolutionary, developmental and homeostatic perspectives.
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              Ex vivo analysis identifies effective HIV-1 latency-reversing drug combinations.

              Reversal of HIV-1 latency by small molecules is a potential cure strategy. This approach will likely require effective drug combinations to achieve high levels of latency reversal. Using resting CD4+ T cells (rCD4s) from infected individuals, we developed an experimental and theoretical framework to identify effective latency-reversing agent (LRA) combinations. Utilizing ex vivo assays for intracellular HIV-1 mRNA and virion production, we compared 2-drug combinations of leading candidate LRAs and identified multiple combinations that effectively reverse latency. We showed that protein kinase C agonists in combination with bromodomain inhibitor JQ1 or histone deacetylase inhibitors robustly induce HIV-1 transcription and virus production when directly compared with maximum reactivation by T cell activation. Using the Bliss independence model to quantitate combined drug effects, we demonstrated that these combinations synergize to induce HIV-1 transcription. This robust latency reversal occurred without release of proinflammatory cytokines by rCD4s. To extend the clinical utility of our findings, we applied a mathematical model that estimates in vivo changes in plasma HIV-1 RNA from ex vivo measurements of virus production. Our study reconciles diverse findings from previous studies, establishes a quantitative experimental approach to evaluate combinatorial LRA efficacy, and presents a model to predict in vivo responses to LRAs.
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                Author and article information

                Contributors
                m.araingaramirez@unmc.edu
                benson.edagwa@unmc.edu
                rlmosley@unmc.edu
                lpoluekt@unmc.edu
                sgorantla@unmc.edu
                402-559-8920 , hegendel@unmc.edu
                Journal
                Retrovirology
                Retrovirology
                Retrovirology
                BioMed Central (London )
                1742-4690
                9 March 2017
                9 March 2017
                2017
                : 14
                : 17
                Affiliations
                ISNI 0000 0001 0666 4105, GRID grid.266813.8, Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, College of Medicine, , University of Nebraska Medical Center, ; Omaha, NE 68198-5880 USA
                Article
                344
                10.1186/s12977-017-0344-7
                5345240
                28279181
                05c72f42-51dc-49a4-b210-0d6cda11be4d
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 19 December 2016
                : 6 March 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: RO1 MH104147
                Award ID: P01 DA028555
                Award ID: R01 NS36126
                Award ID: P01 NS31492
                Award ID: 2R01 NS034239
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Microbiology & Virology
                hiv-1,monocyte–macrophage,humanized mice,antiretroviral therapy,viral reservoirs,t effector cells

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