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

• 成果类型: Article
• 署名作者: Pitchai, Fathima N. Nagoor; Tanner, Elizabeth J.; Khetan, Neha; Vasen, Gustavo; Levrel, Clara; Kumar, Arjun J.; Pandey, Shilpi; Ordonez, Tracy; Barnette, Philip; Spencer, David; Jung, Seung-Yong; Glazier, Joshua; Thompson, Cassandra; Harvey-Vera, Alicia; Son, Hye-In; Strathdee, Steffanie A.; Holguin, Leo; Urak, Ryan; Burnett, John; Burgess, William; Busman-Sahay, Kathleen; Estes, Jacob D.; Hessell, Ann; Fennessey, Christine M.; Keele, Brandon F.; Haigwood, Nancy L.; Weinberger, Leor S.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; The J David Gladstone Institutes; University of Washington; University of Washington Seattle; Oregon Health & Science University; Oregon National Primate Research Center; Washington University (WUSTL); University of California System; University of California San Diego; City of Hope; Beckman Research Institute of City of Hope; University of Miami; Oregon Health & Science University; Aarhus University; Royal Melbourne Institute of Technology (RMIT); National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); Frederick National Laboratory for Cancer Research; University of California System; University of California San Francisco; University of California System; University of California San Francisco
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10177
• DOI: 10.1126/science.adn5866
• 发表日期: 2024-08-09
• 关键词: cd4(+) t-cells; human immunodeficiency viruses; dynamics in-vivo; antiretroviral therapy; lentiviral vectors; rhesus macaques; gene-transfer; monoclonal-antibodies; peripheral-blood; down-regulation

摘要

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 [R0] > 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 >3log10 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.