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


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

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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

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.

Competing interests

The authors declare no competing interests.

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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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.