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Engineered deletions of HIV replicate conditionally to reduce disease in nonhuman primates

Affiliations
  • 1Gladstone Center for Cell Circuitry, University of California, San Francisco, CA, USA.
  • 2Gladstone Institute of Virology, University of California, San Francisco, CA, USA.
  • 3Department of Bioengineering, University of Washington, Seattle, WA, USA.
  • 4Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA.
  • 5Absci Corporation, Vancouver, WA, USA.
  • 6Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
  • 7Global Health Sciences, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
  • 8US-Mexico Border Health Commission, Tijuana, Mexico.
  • 9Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, USA.
  • 10Center for Gene Therapy, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
  • 11Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, USA.
  • 12Faculty of Health, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • 13School of Health and Biomedical Sciences College of Science, Engineering and Health RMIT University, Melbourne, Australia.
  • 14AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 15Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, USA.
  • 16Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA.

Published on:

August 8, 2024

Abstract

Antiviral therapies with reduced frequencies of administration and high barriers to resistance remain a major goal. For HIV, theories have proposed that viral-deletion variants, which conditionally replicate with a basic reproductive ratio [R] > 1 (termed “therapeutic interfering particles” or “TIPs”), could parasitize wild-type virus to constitute single-administration, escape-resistant antiviral therapies. We report the engineering of a TIP that, in rhesus macaques, reduces viremia of a highly pathogenic model of HIV by >3log following a single intravenous injection. Animal lifespan was significantly extended, TIPs conditionally replicated and were continually detected for >6 months, and sequencing data showed no evidence of viral escape. A single TIP injection also suppressed virus replication in humanized mice and cells from persons living with HIV. These data provide proof of concept for a potential new class of single-administration antiviral therapies.