Long-acting capsid inhibitor protects macaques from repeat SHIV challenges

Samuel J. Vidal, Elena Bekerman, Derek Hansen, Bing Lu, Kelly Wang, Judy Mwangi, William Rowe, Federico Campigotto, Jim Zheng, Darryl Kato, Abishek Chandrashekar, Julia Barrett, Shivani Patel, Huahua Wan, Tochi Anioke, Noe B. Mercado, Joseph P. Nkolola, Melissa J. Ferguson, William J. Rinaldi, Christian Callebaut, Wade Blair, Tomas Cihlar, Romas Geleziunas, Stephen R. Yant () and Dan H. Barouch ()
Additional contact information
Samuel J. Vidal: Harvard Medical School
Elena Bekerman: Gilead Sciences
Derek Hansen: Gilead Sciences
Bing Lu: Gilead Sciences
Kelly Wang: Gilead Sciences
Judy Mwangi: Gilead Sciences
William Rowe: Gilead Sciences
Federico Campigotto: Gilead Sciences
Jim Zheng: Gilead Sciences
Darryl Kato: Gilead Sciences
Abishek Chandrashekar: Harvard Medical School
Julia Barrett: Harvard Medical School
Shivani Patel: Harvard Medical School
Huahua Wan: Harvard Medical School
Tochi Anioke: Harvard Medical School
Noe B. Mercado: Harvard Medical School
Joseph P. Nkolola: Harvard Medical School
Melissa J. Ferguson: Alpha Genesis, Inc.
William J. Rinaldi: Alpha Genesis, Inc.
Christian Callebaut: Gilead Sciences
Wade Blair: Gilead Sciences
Tomas Cihlar: Gilead Sciences
Romas Geleziunas: Gilead Sciences
Stephen R. Yant: Gilead Sciences
Dan H. Barouch: Harvard Medical School

Nature, 2022, vol. 601, issue 7894, 612-616

Abstract: Abstract Because no currently available vaccine can prevent HIV infection, pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) is an important tool for combating the HIV pandemic1,2. Long-acting ARVs promise to build on the success of current PrEP strategies, which must be taken daily, by reducing the frequency of administration3. GS-CA1 is a small-molecule HIV capsid inhibitor with picomolar antiviral potency against a broad array of HIV strains, including variants resistant to existing ARVs, and has shown long-acting therapeutic potential in a mouse model of HIV infection4. Here we show that a single subcutaneous administration of GS-CA1 provides long-term protection against repeated rectal simian–human immunodeficiency virus (SHIV) challenges in rhesus macaques. Whereas all control animals became infected after 15 weekly challenges, a single 300 mg kg−1 dose of GS-CA1 provided per-exposure infection risk reduction of 97% for 24 weeks. Pharmacokinetic analysis showed a correlation between GS-CA1 plasma concentration and protection from SHIV challenges. GS-CA1 levels greater than twice the rhesus plasma protein-adjusted 95% effective concentration conferred 100% protection in this model. These proof-of-concept data support the development of capsid inhibitors as a novel long-acting PrEP strategy in humans.

Date: 2022
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DOI: 10.1038/s41586-021-04279-4

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