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HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy

Nature Microbiology volume 4, pages 633–644 (2019)Cite this article

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Abstract

Human immunodeficiency virus type 1 (HIV-1) eradication is prevented by the establishment on infection of cellular HIV-1 reservoirs that are not fully characterized, especially in genital mucosal tissues (the main HIV-1 entry portal on sexual transmission). Here, we show, using penile tissues from HIV-1-infected individuals under suppressive combination antiretroviral therapy, that urethral macrophages contain integrated HIV-1 DNA, RNA, proteins and intact virions in virus-containing compartment-like structures, whereas viral components remain undetectable in urethral T cells. Moreover, urethral cells specifically release replication-competent infectious HIV-1 following reactivation with the macrophage activator lipopolysaccharide, while the T-cell activator phytohaemagglutinin is ineffective. HIV-1 urethral reservoirs localize preferentially in a subset of polarized macrophages that highly expresses the interleukin-1 receptor, CD206 and interleukin-4 receptor, but not CD163. To our knowledge, these results are the first evidence that human urethral tissue macrophages constitute a principal HIV-1 reservoir. Such findings are determinant for therapeutic strategies aimed at HIV-1 eradication.

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Fig. 1: Urethral macrophages contain integrated HIV-1 DNA.
Fig. 2: Selective outgrowth of replication-competent infectious HIV-1 is reactivated from urethral macrophages by LPS.
Fig. 3: Urethral macrophages contain HIV-1 RNA.
Fig. 4: Urethral macrophages enclose HIV-1 proteins and virions.
Fig. 5: Urethral macrophage reservoirs have a distinct polarization phenotype, while urethral T cells are not prone to contain HIV-1 reservoirs.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon request.

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Acknowledgements

The authors thank J. P. Wolf (Reproductive Biology, Hôpital Cochin, AP-HP, Paris, France) for helpful discussion. This study was supported by grants from l’Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) to M.B. (ANRS-2014AO21038) and A.H. (ANRS-2016AO11023), and from the French Government’s Investissement d’Avenir programme, Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (ANR-10-LABX-62-IBEID) to A.H. C.-A.D., F.R. and J.-P.J. were supported by ANRS. F.R. was supported by SIDACTION. L.X. was supported by the China Scholarship Council.

Author information

Author notes

  1. Charles-Antoine Dutertre

    Present address: Program in Emerging Infectious Disease, Duke–National University of Singapore Medical School, Singapore, Singapore

  2. These authors contributed equally: Fernando Real, Alexis Sennepin.

Authors and Affiliations

  1. Laboratory of Mucosal Entry of HIV-1 and Mucosal Immunity, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR8104, Paris, France

    Yonatan Ganor, Fernando Real, Alexis Sennepin, Lin Xu, Daniela Tudor, Sabrina Marion, Ali-Redha Zenak, Zhicheng Zhou & Morgane Bomsel

  2. INSERM U1016, Paris, France

    Yonatan Ganor, Fernando Real, Alexis Sennepin, Charles-Antoine Dutertre, Lin Xu, Daniela Tudor, Bénédicte Charmeteau, Anne Couedel-Courteille, Sabrina Marion, Ali-Redha Zenak, Jean-Pierre Jourdain, Zhicheng Zhou, Alain Schmitt, Rémi Cheynier, Anne Hosmalin & Morgane Bomsel

  3. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Yonatan Ganor, Fernando Real, Alexis Sennepin, Charles-Antoine Dutertre, Lin Xu, Daniela Tudor, Bénédicte Charmeteau, Anne Couedel-Courteille, Sabrina Marion, Ali-Redha Zenak, Jean-Pierre Jourdain, Zhicheng Zhou, Alain Schmitt, Rémi Cheynier, Anne Hosmalin & Morgane Bomsel

  4. Laboratory of Dendritic Cell Immunobiology, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR8104, Paris, France

    Charles-Antoine Dutertre, Jean-Pierre Jourdain & Anne Hosmalin

  5. Public Health Research Institute, Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, USA

    Lisa Prevedel & Eliseo A Eugenin

  6. Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers University, Newark, NJ, USA

    Lisa Prevedel & Eliseo A Eugenin

  7. Laboratory of Cytokines and Viral Infections, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR8104, Paris, France

    Bénédicte Charmeteau, Anne Couedel-Courteille & Rémi Cheynier

  8. Electron Microscopy Platform Laboratory, Department of Infection, Immunity and Inflammation, Cochin Institute, CNRS UMR8104, Paris, France

    Alain Schmitt

  9. Hematology and Immunology Service, Ambroise Paré Hospital, Boulogne, France

    Claude Capron

  10. Plastic, Reconstructive and Aesthetic Surgery Department, Saint Louis Hospital, Paris, France

    Marc Revol & Sarra Cristofari

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Contributions

Y.G. and M.B. conceived the study, designed the experiments and wrote the paper. Y.G. performed the majority of the experiments. A.S., F.R., C.-A.D., J.-P.J. and Z.Z. performed the flow cytometry experiments, which were designed by A.H. F.R. and S.M. performed the p24 staining and confocal microscopy experiments. A.S., L.X., D.T., B.C. and A.C.-C. performed the PCR experiments, which were designed by R.C. L.P. and E.A.E. performed and designed the DNA FISH experiments. A.-R.Z. performed the immunohistochemistry experiments. M.R. and S.C. provided the penile tissues. A.S. performed the electron microscopy experiments. C.C. provided T cells from HIV-1-infected patients under suppressive cART.

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Correspondence to Yonatan Ganor or Morgane Bomsel.

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Supplementary Figures 1–7 and Supplementary Tables 1–2.

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High resolution original images obtained by microscopy used to build panels.

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Ganor, Y., Real, F., Sennepin, A. et al. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nat Microbiol 4, 633–644 (2019). https://doi.org/10.1038/s41564-018-0335-z

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