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    HIV-1 reservoirs in macrophages: the myth becomes reality

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    A study diriged by Morgane Bomsel

    A major obstacle preventing HIV-1 eradication is the presence, in HIV-1-infected patients under suppressive antiretroviral therapy, of cellular reservoirs containing latent virus. In a study published in Nature Microbiology, a research team from the Cochin Institute (INSERM/CNRS/Paris Descartes University) supported by grants from ANRS and SIDACTION, and coordinated by Morgane Bomsel, a research director at CNRS, shows that in such patients macrophages residing within the penis constitute genuine HIV-1 cellular reservoirs. The discovery of this novel type of HIV-1 reservoir in tissue macrophages has important clinical implications.

     

    © Morgane Bomsel, Yonatan Ganor & Fernando RealCellular reservoirs are cell populations infected by the human immunodeficiency virus type 1 (HIV-1) that do not produce infectious virus due to anti-retroviral therapy. Yet, HIV-1 remains latent in these cells and rebounds rapidly following therapy interruption. Most studies on HIV-1 reservoirs focused on that found in circulation T-cells. Attempts to eradicate HIV-1 from these T-cell reservoirs consisted of re-activating the latent virus, by strategies termed ‘shock and kill’. These strategies aim at re-activating the latently infected cells in order to expose them to the immune system, which would subsequently be eliminated by the patients’ own cytotoxic T-cells, in the presence of antiretroviral agents and/or HIV-1 neutralizing antibodies. To date, all these attempt failed.

    Moreover, comparison of the genetic sequences of the virus from T-cell reservoirs and that of residual viremia and/or rebounding virus showed that some virus originates from a cellular source other than T-cells. These observations suggest the existence of HIV-1 reservoirs in additional cells that are also targeted by HIV-1. Macrophages are an ideal candidate, as they are rapidly targeted by HIV-1 upon its mucosal sexual transmission but resist HIV-1 cytopathic effects.

    The researchers focused on potential reservoirs in penile tissues, obtained from n=20 HIV-1-infected patients under suppressive antiretroviral therapy with undetectable plasma viral loads, undergoing elective gender reassignment. They compared the capacity of macrophages and T-cells to be re-activated and produce infectious virus. Using urethral tissues obtained from these patients, the researches first prepared single-cell suspensions that were subsequently sorted into CD68-positive macrophages and CD3-positive T-cells. Using PCR, HIV-1 DNA was found integrated only into the genome of macrophages, but not T-cells. In addition, production of infectious HIV-1 could be re-activated only from macrophages specifically re-activated with LPS, while specific T-cell re-activation with PHA remained ineffective. Finally, these macrophage reservoirs were phenotypically characterized: they represent a new sub-population of polarized macrophages, expressing CD206, IL-1R and IL-4R but not CD163, and are enriched in urethral tissues of these patients.

    The researchers could hence demonstrate that in contrast to the accepted dogma, that HIV-1 reservoirs reside principally in T-cells, macrophages constitute a major HIV-1 reservoir within the urethral penile mucosa. The researchers hypothesize that ‘As urethral macrophages are the first cells targeted by HIV-1 upon its sexual transmission, macrophage reservoirs could be established very rapidly, already during the early events of HIV-1 transmission’.

    The study is the first to demonstrate the existence of inducible HIV-1 reservoirs in human tissue macrophages. Systemic investigations of the presence of inducible HIV-1 reservoirs in other human mucosal and lymphoid tissues are now needed. This information would be necessary and crucial for future ‘shock and kill’ strategies aimed at reservoir elimination, a clinical goal that is still unmet.

     

    Figure

    “HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy”
    Yonatan Ganor, Fernando Real, Alexis Sennepin, Charles-Antoine Dutertre, Lisa Prevedel, Lin Xu, Daniela Tudor, Bénédicte Charmeteau, Anne Couedel-Courteille, Sabrina Marion, Ali-Redha Zenak, Jean-Pierre Jourdain, Zhicheng Zhou, Alain Schmitt, Claude Capron, Eliseo A Eugenin, Rémi Cheynier, Marc Revol, Sarra Cristofari, Anne Hosmalin, Morgane Bomsel.
    Nature Microbiology, 2019
    http://dx.doi.org/10.1038/s41564-018-0335-z

    © Morgane Bomsel, Yonatan Ganor & Fernando Real

     

    For more information

    Yonatan Ganor, Fernando Real, Alexis Sennepin, Charles-Antoine Dutertre, Lisa Prevedel, Lin Xu, Daniela Tudor, Bénédicte Charmeteau, Anne Couedel-Courteille, Sabrina Marion, Ali-Redha Zenak, Jean-Pierre Jourdain, Zhicheng Zhou, Alain Schmitt, Claude Capron, Eliseo A Eugenin, Rémi Cheynier, Marc Revol, Sarra Cristofari, Anne Hosmalin, Morgane Bomsel. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nature Microbiology, 2019.  DOI: 10.1038/s41564-018-0335-z 

     

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