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 Ferguson, William Rinaldi, Christian Callebaut, Wade Blair, Tomáš Cihlář, Romas Geleziunas, Stephen R. Yant, Dan H. Barouch
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 pandemic 1,2 . Long-acting ARVs promise to build on the success of current PrEP strategies, which must be taken daily, by reducing the frequency of administration 3 . 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 infection 4 . 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.