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

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.

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.

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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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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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