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HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy

Nature Medicine volume 23, pages 638–643 (2017)Cite this article

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Abstract

Despite years of fully suppressive antiretroviral therapy (ART), HIV persists in its hosts and is never eradicated. One major barrier to eradication is that the virus infects multiple cell types that may individually contribute to HIV persistence. Tissue macrophages are critical contributors to HIV pathogenesis1,2,3; however, their specific role in HIV persistence during long-term suppressive ART has not been established4,5,6. Using humanized myeloid-only mice (MoM), we demonstrate that HIV infection of tissue macrophages is rapidly suppressed by ART, as reflected by a rapid drop in plasma viral load and a dramatic decrease in the levels of cell-associated viral RNA and DNA. No viral rebound was observed in the plasma of 67% of the ART-treated animals at 7 weeks after ART interruption, and no replication-competent virus was rescued from the tissue macrophages obtained from these animals. In contrast, in a subset of animals (∼33%), a delayed viral rebound was observed that is consistent with the establishment of persistent infection in tissue macrophages. These observations represent the first direct evidence, to our knowledge, of HIV persistence in tissue macrophages in vivo.

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Figure 1: Viral suppression, persistence, and rebound induced by structured ART interruption in BLT mice.
Figure 2: ART rapidly suppresses viral replication in MoM.
Figure 3: HIV persistence in tissue macrophages during ART.

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Acknowledgements

We thank N. Archin (University of North Carolina at Chapel Hill) for providing the CD8+-depleted feeder cells for in vitro viral outgrowth analysis; J. Kappes and C. Ochsenbauer (University of Alabama at Birmingham) for providing CH040 (11740) via the AIDS Research and Reference Reagent Program; R. Swanstrom (University of North Carolina at Chapel Hill) for providing 4013-env for use in our studies; J. Clements, R. Siliciano, and D. Margolis for their intellectual input in these studies; M. Cohen, B. Haynes, S. Lemon, A. Wahl, and M. Kovarova for their comments and suggestions regarding this manuscript; and former and current members of the Garcia laboratory and the husbandry technicians at the UNC Division of Laboratory Animal Medicine for their assistance. J.V.G. was supported by grants from the National Institute of Mental Health (MH-108179) and the National Institute of Allergy and Infectious Diseases (NIAID) (AI-111899) and by the UNC CFAR (P30 AI050410). Research reported in this publication was also supported by CARE, a Martin Delaney Collaboratory, the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH) of the National Institutes of Health, grant number 1UM1AI126619-01 (J.V.G. and D.D.R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. J.B.H. was supported in part by the Virology Training Grant (T32 AI-007419). R.M.R. was supported by the NIAID (R01 AI-104373). D.D.R. was also supported by the BEAT-HIV Delaney Collaboration (1UM1AI126620), the UCSD CFAR (AI306214), the Department of Veterans Affairs, and the James B. Pendleton Charitable Trust. The funders had no part in study design, data collection or analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA

    Jenna B Honeycutt, William O Thayer, Caroline E Baker, Rachel A Cleary & J Victor Garcia

  2. Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA

    Ruy M Ribeiro & Youfang Cao

  3. Veterans Affairs, San Diego Healthcare System, San Diego, California, USA

    Steven M Lada & Douglas D Richman

  4. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA

    Michael G Hudgens

  5. Department of Medicine, University of California, San Diego, San Diego, California, USA

    Douglas D Richman

  6. Department of Pathology, University of California, San Diego, San Diego, California, USA

    Douglas D Richman

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  1. Jenna B Honeycutt
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Contributions

J.B.H. provided the experimental design, collected and processed blood and tissue samples from mice, prepared viral stocks, performed viral inoculations, administered ART, and performed flow cytometric analyses. W.O.T. processed blood and tissue samples from mice, prepared the injectable ART formulation, and administered ART. C.E.B. provided RNA and DNA analysis, prepared the injectable ART formulation, and processed tissue samples. R.A.C. performed immunohistochemical analysis of tissues. S.M.L. and D.D.R. performed the integrated DNA analysis and analyzed the results. J.B.H., R.M.R., Y.C., and M.G.H. analyzed the data and wrote the manuscript. J.V.G. conceived the study, designed and coordinated the study, and wrote the manuscript.

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Correspondence to J Victor Garcia.

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Honeycutt, J., Thayer, W., Baker, C. et al. HIV persistence in tissue macrophages of humanized myeloid-only mice during antiretroviral therapy. Nat Med 23, 638–643 (2017). https://doi.org/10.1038/nm.4319

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