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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 references 79

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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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            HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation.

            HIV persists in a reservoir of latently infected CD4(+) T cells in individuals treated with highly active antiretroviral therapy (HAART). Here we identify central memory (T(CM)) and transitional memory (T(TM)) CD4(+) T cells as the major cellular reservoirs for HIV and find that viral persistence is ensured by two different mechanisms. HIV primarily persists in T(CM) cells in subjects showing reconstitution of the CD4(+) compartment upon HAART. This reservoir is maintained through T cell survival and low-level antigen-driven proliferation and is slowly depleted with time. In contrast, proviral DNA is preferentially detected in T(TM) cells from aviremic individuals with low CD4(+) counts and higher amounts of interleukin-7-mediated homeostatic proliferation, a mechanism that ensures the persistence of these cells. Our results suggest that viral eradication might be achieved through the combined use of strategic interventions targeting viral replication and, as in cancer, drugs that interfere with the self renewal and persistence of proliferating memory T cells.
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              Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection.

              Human and simian immunodeficiency virus (HIV and SIV) replicate optimally in activated memory CD4(+) T cells, a cell type that is abundant in the intestine. SIV infection of rhesus monkeys resulted in profound and selective depletion of CD4+ T cells in the intestine within days of infection, before any such changes in peripheral lymphoid tissues. The loss of CD4+ T cells in the intestine occurred coincident with productive infection of large numbers of mononuclear cells at this site. The intestine appears to be a major target for SIV replication and the major site of CD4+ T cell loss in early SIV infection.
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                Author and article information

                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
                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
                28279181 5345240 344 10.1186/s12977-017-0344-7
                © 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.

                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 :
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                Research
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                © The Author(s) 2017

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