Multiomic analysis of ART-interruption cohorts identifies cell-extrinsic and -intrinsic mechanisms driving lymphocyte-mediated control of HIV rebound

Tongcui Ma; Ashley F George; Zichong Li; Reuben Thomas; Kailin Yin; Min-Gyoung Shin; Mauricio Montano; Yusuke Matsui; Manickam Ashokkumar; Kyrlia Young; Julia Prigann; Julie Frouard; Sabrina Leddy; Maisha Adiba; Christina Herrde; Ulrike C Lange; Cedric Feschotte; Douglas F Nixon; Edward P Browne; Nancie M Archin; Jonathan Z Li; Davey Smith; Steven Deeks; Ole S Søgaard; Martin Tolstrup; Sulggi Lee; Satish K Pillai; Mohamed Abdel-Mohsen; Katherine S Pollard; Robert Siliciano; Melanie Ott; Warner C Greene; Nadia R Roan

doi:10.1016/j.immuni.2026.01.029

Multiomic analysis of ART-interruption cohorts identifies cell-extrinsic and -intrinsic mechanisms driving lymphocyte-mediated control of HIV rebound

Immunity. 2026 May 12;59(5):1454-1472.e9. doi: 10.1016/j.immuni.2026.01.029. Epub 2026 Mar 20.

Authors

Tongcui Ma¹, Ashley F George¹, Zichong Li², Reuben Thomas², Kailin Yin¹, Min-Gyoung Shin², Mauricio Montano², Yusuke Matsui², Manickam Ashokkumar³, Kyrlia Young¹, Julia Prigann², Julie Frouard¹, Sabrina Leddy⁴, Maisha Adiba⁵, Christina Herrde⁵, Ulrike C Lange⁶, Cedric Feschotte⁴, Douglas F Nixon⁷, Edward P Browne³, Nancie M Archin³, Jonathan Z Li⁸, Davey Smith⁹, Steven Deeks¹⁰, Ole S Søgaard¹¹, Martin Tolstrup¹¹, Sulggi Lee¹⁰, Satish K Pillai¹², Mohamed Abdel-Mohsen¹³, Katherine S Pollard¹⁴, Robert Siliciano¹⁵, Melanie Ott¹⁶, Warner C Greene¹⁷, Nadia R Roan¹⁸

Affiliations

¹ Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, San Francisco, CA 94158, USA.
² Gladstone Institutes, San Francisco, CA 94158, USA.
³ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
⁵ Leibniz Institute of Virology, Hamburg, Germany.
⁶ Leibniz Institute of Virology, Hamburg, Germany; Institute of Infection Research and Vaccine Development, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁷ Institute of Translational Research, Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA.
⁸ Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁹ School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁰ University of California, San Francisco, San Francisco, CA 94158, USA.
¹¹ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹² University of California, San Francisco, San Francisco, CA 94158, USA; Vitalant Research Institute, San Francisco, CA 94105, USA.
¹³ Division of Infectious Diseases, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Center for Human Immunobiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Potocsnak Longevity Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
¹⁴ Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, San Francisco, CA 94158, USA; Biohub, San Francisco, CA 94158, USA.
¹⁵ Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹⁶ Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, San Francisco, CA 94158, USA; Biohub, San Francisco, CA 94158, USA. Electronic address: melanie.ott@gladstone.ucsf.edu.
¹⁷ Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: warner.greene@gladstone.ucsf.edu.
¹⁸ Gladstone Institutes, San Francisco, CA 94158, USA; University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: nadia.roan@gladstone.ucsf.edu.

Abstract

Immunological mechanisms regulating HIV rebound after antiretroviral therapy (ART) interruption remain unclear. We examined relationships between host factors, HIV reservoir, and HIV time-to-rebound after analytical treatment interruption (ATI) by characterizing pre-ATI peripheral blood mononuclear cells (PBMCs) from 75 ART-suppressed people with HIV (PWH) using high-parameter methods. Across interventional (CLEAR, TEACH, and REDUC) and non-interventional (A5345) cohorts, delayed rebound was not associated with intact HIV. Cohort-specific immune effectors were associated with delayed rebound. RNA sequencing of CD4⁺ T cells from A5345 revealed that the mTOR inhibitor DDIT4 and zinc finger protein ZNF254 were associated with delayed rebound. In vitro and in vivo studies demonstrated that DDIT4 and ZNF254 suppressed HIV expression. Metformin induced DDIT4 and suppressed HIV expression in primary cells and cells from ART-suppressed PWH, suggesting that this affordable diabetes drug could be repurposed to silence HIV. Our results support the pursuit of both immune- and HIV-silencing strategies to achieve ART-free HIV remission.

Keywords: CD4(+) T cells; HIV persistence; NK cells; T cells; metformin; zinc finger transcription factor.

MeSH terms

Animals
Anti-HIV Agents / therapeutic use
CD4-Positive T-Lymphocytes* / drug effects
CD4-Positive T-Lymphocytes* / immunology
CD4-Positive T-Lymphocytes* / virology
Cohort Studies
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Female
HIV Infections* / drug therapy
HIV Infections* / immunology
HIV Infections* / virology
HIV-1* / drug effects
HIV-1* / immunology
HIV-1* / physiology
Humans
Male
Metformin / pharmacology
Metformin / therapeutic use
Transcription Factors / genetics
Transcription Factors / metabolism
Treatment Interruption
Viral Load / drug effects

Substances

Transcription Factors
DDIT4 protein, human
Metformin
DNA-Binding Proteins
Anti-HIV Agents

Abstract

MeSH terms

Substances

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