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

Topic/Product:
Immunology, Inflammation Panel 250
Disease Area:
HIV
Sample Type:
Plasma

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.

Authors & Affiliations

Tongcui Ma¹˒²˒¹⁷, Ashley F. George¹˒²˒¹⁷, Zichong Li¹, Reuben Thomas¹, Kailin Yin¹˒², Min-Gyoung Shin¹, Mauricio Montano¹, Yusuke Matsui¹, Manickam Ashokkumar³, Kyrlia Young¹˒², Julia Prigann¹, Julie Frouard¹˒², Sabrina Leddy⁴, Maisha Adiba⁵, Christina Herrde⁵, Ulrike C. Lange⁵˒⁶, Cedric Feschotte⁴, Douglas F. Nixon⁷, Edward P. Browne³, Nancie M. Archin³, Jonathan Z. Li⁸, Davey Smith⁹, Steven Deeks², Ole S. Søgaard¹⁰, Martin Tolstrup¹⁰, Sulggi Lee², Satish K. Pillai²˒¹¹, Mohamed Abdel-Mohsen¹²˒¹³˒¹⁴, Katherine S. Pollard¹˒²˒¹⁵, Robert Siliciano¹⁶, Melanie Ott* ¹˒²˒¹⁵, Warner C. Greene* ¹˒², and Nadia R. Roan* ¹˒²˒¹⁸

¹ Gladstone Institutes, San Francisco, CA 94158, USA
² University of California, San Francisco, 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 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 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
¹¹ Vitalant Research Institute, San Francisco, CA 94105, USA
¹² Division of Infectious Diseases, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
¹³ Center for Human Immunobiology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
¹⁴ Potocsnak Longevity Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
¹⁵ Biohub, San Francisco, CA 94158, USA
¹⁶ Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
¹⁷ These authors contributed equally
¹⁸ Lead contact

Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.