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Immune reconstitution inflammatory syndrome drives emergence of HIV drug resistance from multiple anatomic compartments in a person living with HIV

Nature Medicine volume 29, pages 1364–1369 (2023)Cite this article

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Abstract

Reservoirs of HIV maintained in anatomic compartments during antiretroviral therapy prevent HIV eradication. However, mechanisms driving their persistence and interventions to control them remain elusive. Here we report the presence of an inducible HIV reservoir within antigen-specific CD4+T cells in the central nervous system of a 59-year-old male with progressive multifocal leukoencephalopathy immune reconstitution inflammatory syndrome (PML-IRIS). HIV production during PML-IRIS was suppressed by modulating inflammation with corticosteroids; selection of HIV drug resistance caused subsequent breakthrough viremia. Therefore, inflammation can influence the composition, distribution and induction of HIV reservoirs, warranting it as a key consideration for developing effective HIV remission strategies.

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Fig. 1: Clinical history.
Fig. 2: Immunological and virological characteristics of PML-IRIS.

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Data availability

pro-RT, IN and env sequences are publicly available (GenBank accession numbers OQ924993-OQ925343, OM937385-OM937739 and OQ925344-OQ925389, respectively). All other data are included in the paper and supplementary documents.

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Acknowledgements

The authors thank the staff of the National Institutes of Health (NIH) Clincal Center inpatient and outpatient services, the National Institute of Allergy and Infectious Diseases research staff and the study participant for their important contributions, without whom this research would not have been possible. We also thank E. Bruzzesi for contributions in the laboratory. This research was supported, in part, by the Intramural Research Program of the NIH and, in part, with federal funds from the National Cancer Institute under contract number 75N91019D00024/HHSN261201500003I as well as the Office of AIDS Research under the strategic funds supplement: ‘Impact of lymphopenia and co-infections on residual inflammation and reservoirs’. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

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Author notes

  1. Camille Lange

    Present address: Military HIV Research Program, Walter Reed Army Institute of Research, Henry M. Jackson Foundation for the Advancement of Military Medicine, Silver Spring, MD, USA

  2. These authors contributed equally: Andrea Lisco, Camille Lange, Frank Maldarelli, Irini Sereti.

Authors and Affiliations

  1. Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    Andrea Lisco, Maura Manion, Catherine Rehm, Peiying Ye, Katherine M. Bricker & Irini Sereti

  2. Clinical Retrovirology Section, HIV Dynamics and Replication Program National Cancer Institute, National Institutes of Health, Frederick, MD, USA

    Camille Lange, Kristi Huik, Natalie Lindo & Frank Maldarelli

  3. Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Bethesda, MD, USA

    Safia Kuriakose

  4. Virus Isolation and Serology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Robin Dewar

  5. AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Robert J. Gorelick, Brandon F. Keele & Christine M. Fennessey

  6. Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Quan Yu & Pawel Muranski

  7. Center for Infectious Disease Imaging, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD, USA

    Dima A. Hammoud

  8. Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Bryan R. Smith

  9. Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Brad T. Sherman

  10. Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Craig Sykes

Authors
  1. Andrea Lisco
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Contributions

A.L., C.M.L., F.M. and I.S. conceived and planned the experiments. A.L., M.M., S.K., D.A.H. and I.S. provided clinical care. A.L., C.M.L., S.K., R.D., R.J.G., Q.Y., D.H., N.L., P.Y., K.B. and C.M.F. carried out the experiments. C.M.L., A.L., B.R., C.R., B.S., C.S., R.J.G., K.H. and N.L. contributed to sample preparation. A.L., C.M.L., M.M., F.M., I.S., R.J.G., B.K., C.M.F. and P.M. contributed to the interpretation of the results. C.M.L. took the lead in writing the initial draft of the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

Corresponding authors

Correspondence to Camille Lange, Frank Maldarelli or Irini Sereti.

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The authors declare no competing interests.

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Nature Medicine thanks Janice Clements and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Alison Farrell, in collaboration with the Nature Medicine team.

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Supplementary Figs. 1–7 and Supplementary Tables 1–3.

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Lisco, A., Lange, C., Manion, M. et al. Immune reconstitution inflammatory syndrome drives emergence of HIV drug resistance from multiple anatomic compartments in a person living with HIV. Nat Med 29, 1364–1369 (2023). https://doi.org/10.1038/s41591-023-02387-4

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