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

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Engineered deletions of HIV replicate conditionally to reduce disease in nonhuman primates
Science ( IF 44.7 ) Pub Date : 2024-08-08 , DOI: 10.1126/science.adn5866
Fathima N Nagoor Pitchai _{1,

2} , Elizabeth J Tanner _{1,

2} , Neha Khetan _{1,

2} , Gustavo Vasen _{1,

2} , Clara Levrel _{1,

2} , Arjun J Kumar _{1,

2,

3} , Shilpi Pandey ₄ , Tracy Ordonez ₄ , Philip Barnette ₄ , David Spencer _{4,

5} , Seung-Yong Jung ₁ , Joshua Glazier ₁ , Cassandra Thompson _{1,

6} , Alicia Harvey-Vera , Hye-In Son _{7,

8,

9} , Hye-In Son ₁ , Steffanie A Strathdee ₇ , Leo Holguin ₇ , Ryan Urak ₁₀ , John Burnett _{10,

11} , William Burgess ₉ , Kathleen Busman-Sahay ₉ , Jacob D Estes _{9,

12,

13} , Ann Hessell ₄ , Christine M Fennessey ₁₄ , Brandon F Keele ₁₄ , Nancy L Haigwood ₄ , Leor S Weinberger _{1,

2,

15,

16}

Affiliation

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

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 0 ] > 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 10 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.

中文翻译：

HIV的工程删除有条件地复制以减少非人类灵长类动物的疾病

减少给药频率和提高耐药性的抗病毒疗法仍然是一个主要目标。对于HIV，理论提出，病毒缺失变体以基本繁殖率[R 0 ] > 1（称为“治疗干扰颗粒”或“TIP”）有条件地复制，可以寄生野生型病毒以构成单一病毒。管理，逃避抗病毒治疗。我们报告了 TIP 的工程设计，在恒河猴中，单次静脉注射后，可将高致病性 HIV 模型的病毒血症减少 >3log 10。动物寿命显着延长，TIP 有条件复制并持续检测到 >6 个月，测序数据显示没有病毒逃逸的证据。单次 TIP 注射也抑制了人源化小鼠和 HIV 感染者细胞中的病毒复制。这些数据为潜在的新型单次给药抗病毒疗法提供了概念证明。

更新日期：2024-08-08

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