Long-acting capsid inhibitor protects macaques from repeat SHIV challenges

Samuel J Vidal,Wade Blair,William Rowe,Shivani Patel,Derek Hansen,Jim Zheng,Julia Barrett,Stephen R Yant,Melissa Ferguson ,Huahua Wan,Federico Campigotto,Judy Mwangi,Kelly Wang,Noe B Mercado,Christian Callebaut,Tomáš Cihlář ,Elena Bekerman,Abishek Chandrashekar,William Rinaldi ,Joseph P Nkolola,Romas Geleziunas,Bing Lu,Tochi Anioke,Darryl Kato,Dan H Barouch

doi:10.1038/s41586-021-04279-4

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.

Highlights

This is a PDF file of a peer-reviewed paper that has been accepted for publication
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
We investigated the relationship between GS-CA1 plasma concentrations and protection against SHIV challenge

Summary

E Cite this article as

We assessed the potential of a single dose of long-acting capsid inhibitor to offer protection against repeated challenges with simian-human immunodeficiency virus (SHIV) in rhesus macaques. To evaluate potential development of resistance against GS-CA1 in measured 0.7x and 1.1x its human paEC95, respectively, both of which particular during the washout phase, a longitudinal population-level sequence analysis of the SHIV gag region encoding CA in rhesus plasma was performed (Extended Data Fig. 4). Our data demonstrate for the first time that a single subcutaneous administration of the capsid inhibitor GS-CA1 provides long-term protection against SHIV infection in rhesus macaques. Quantification was by radiochromatographic peak area using Dionex (Thermo Scientific) Chromeleon 6.8 software

D Cell culture

E Plasma viral load assay

Findings

Statistical methods