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 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.

由于目前没有可用的疫苗可以预防 HIV 感染，因此使用抗逆转录病毒药物 (ARV) 进行暴露前预防 (PrEP) 是对抗 HIV 大流行的重要工具^1,2。长效抗逆转录病毒药物有望在当前 PrEP 策略的成功基础上，通过减少给药频率³来每天采取这些策略。GS-CA1 是一种小分子 HIV 衣壳抑制剂，对多种 HIV 毒株（包括对现有 ARV 耐药的变体）具有皮摩尔级抗病毒效力，并在 HIV 感染小鼠模型中显示出长效治疗潜力⁴. 在这里，我们表明，单次皮下给药 GS-CA1 可提供针对恒河猴反复直肠猿人免疫缺陷病毒 (SHIV) 挑战的长期保护。虽然所有对照动物在 15 周攻击后都受到感染，但单次 300 mg kg ^{- 1}剂量的 GS-CA1 可在 24 周内将每次暴露的感染风险降低 97%。药代动力学分析显示 GS-CA1 血浆浓度与 SHIV 攻击保护之间存在相关性。GS-CA1 水平大于恒河猴血浆蛋白调整的 95% 有效浓度的两倍，在该模型中提供了 100% 的保护。这些概念验证数据支持将衣壳抑制剂开发为一种新型的人类长效 PrEP 策略。