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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Bozzi, G. et al. No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: implications for HIV eradication. Sci. Adv. 5, eaav2045 (2019).
Chaillon, A. et al. HIV persists throughout deep tissues with repopulation from multiple anatomical sources. J. Clin. Invest. 130, 1699–1712 (2020).
Joseph, S. B. et al. Human immunodeficiency virus type 1 RNA detected in the central nervous system (CNS) after years of suppressive antiretroviral therapy can originate from a replicating CNS reservoir or clonally expanded cells. Clin. Infect. Dis. 69, 1345–1352 (2019).
Woodburn, B. M. et al. Characterization of macrophage-tropic HIV-1 infection of central nervous system cells and the influence of inflammation. J. Virol. 96, e0095722 (2022).
Deeks, S. G. et al. Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021. Nat. Med. 27, 2085–2098 (2021).
Giacomini, P. S. et al. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N. Engl. J. Med. 370, 486–488 (2014).
Mullins, C., Miranda, J., Sandoval, H., Ramos-Duran, L. & Tonarelli, S. B. The benefit of mirtazapine in the treatment of progressive multifocal leukoencephalopathy in a young HIV-positive patient: a case report. Innov. Clin. Neurosci. 15, 33–35 (2018).
Gele, T. et al. Cerebrospinal fluid exposure to bictegravir/emtricitabine/tenofovir in HIV-1-infected patients with CNS impairment. J. Antimicrob. Chemother. 76, 3280–3285 (2021).
Gunst, J. D., Hojen, J. F. & Sogaard, O. S. Broadly neutralizing antibodies combined with latency-reversing agents or immune modulators as strategy for HIV-1 remission. Curr. Opin. HIV AIDS 15, 309–315 (2020).
Wiegand, A. et al. Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART. Proc. Natl Acad. Sci. USA 114, E3659–E3668 (2017).
Coffin, J. M. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science 267, 483–489 (1995).
Simonetti, F. R. et al. Antigen-driven clonal selection shapes the persistence of HIV-1-infected CD4+ T cells in vivo. J. Clin. Invest. 131, e145254 (2021).
Kincer, L. et al. HIV-1 is transported into the central nervous system by trafficking infected cells. Pathog. Immun. 7, 131–142 (2023).
Sereti, I. et al. Prospective international study of incidence and predictors of immune reconstitution inflammatory syndrome and death in people living with human immunodeficiency virus and severe lymphopenia. Clin. Infect. Dis. 71, 652–660 (2020).
Mendoza, P. et al. Antigen-responsive CD4+ T cell clones contribute to the HIV-1 latent reservoir. J. Exp. Med. 217, e20200051 (2020).
Gavegnano, C. et al. Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors. PLoS Pathog. 13, e1006740 (2017).
Uldrick, T. S. et al. Pembrolizumab induces HIV latency reversal in people living with HIV and cancer on antiretroviral therapy. Sci. Transl. Med. 14, eabl3836 (2022).
Chiu, C. Y. et al. Combination immune checkpoint blockade enhances IL-2 and CD107a production from HIV-specific T cells ex vivo in people living with HIV on antiretroviral therapy. J. Immunol. 208, 54–62 (2022).
Hsu, D. C., Mellors, J. W. & Vasan, S. Can broadly neutralizing HIV-1 antibodies help achieve an ART-free remission? Front. Immunol. 12, 710044 (2021).
Simonetti, F. R. et al. Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo. Proc. Natl Acad. Sci. USA 113, 1883–1888 (2016).
Somsouk, M. et al. The immunologic effects of mesalamine in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized crossover trial. PLoS ONE 9, e116306 (2014).
Pardons, M. et al. Single-cell characterization and quantification of translation-competent viral reservoirs in treated and untreated HIV infection. PLoS Pathog. 15, e1007619 (2019).
Palmer, S. et al. Multiple, linked human immunodeficiency virus type 1 drug resistance mutations in treatment-experienced patients are missed by standard genotype analysis. J. Clin. Microbiol. 43, 406–413 (2005).
Keele, B. F. et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc. Natl Acad. Sci. USA 105, 7552–7557 (2008).
Achaz, G. et al. A robust measure of HIV-1 population turnover within chronically infected individuals. Mol. Biol. Evol. 21, 1902–1912 (2004).
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.
Author information
Authors and Affiliations
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
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
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.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary Figs. 1–7 and Supplementary Tables 1–3.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41591-023-02387-4
This article is cited by
-
Antiretrovirals/prednisone
Reactions Weekly (2023)