Gilead Sciences, Foster City, California, United States of America.
Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
PLoS Pathog. 2022 Apr 22;18(4):e1010467. doi: 10.1371/journal.ppat.1010467. eCollection 2022 Apr.
A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like receptor 7 (TLR7) agonists and broadly neutralizing antibodies (bNAbs) have shown delay or prevention of viral rebound following antiretroviral therapy (ART) discontinuation in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques. In these prior studies, ART was initiated early during acute infection, which limited the size and diversity of the viral reservoir. Here we evaluated in SHIV-infected rhesus macaques that did not initiate ART until 1 year into chronic infection whether the TLR7 agonist vesatolimod in combination with the bNAb PGT121, formatted either as a human IgG1, an effector enhanced IgG1, or an anti-CD3 bispecific antibody, would delay or prevent viral rebound following ART discontinuation. We found that all 3 antibody formats in combination with vesatolimod were able to prevent viral rebound following ART discontinuation in a subset of animals. These data indicate that a TLR7 agonist combined with antibodies may be a promising strategy to achieve long-term ART-free HIV remission in humans.
开发治愈 HIV-1 感染的方法面临的一个主要挑战是在早期感染期间建立的持续存在的病毒储存库。先前使用 Toll 样受体 7(TLR7)激动剂和广泛中和抗体(bNAb)的研究表明,在感染猴免疫缺陷病毒(SHIV)的恒河猴中停止抗逆转录病毒治疗(ART)后,病毒会延迟或预防反弹。在这些先前的研究中,ART 在急性感染早期开始,这限制了病毒储存库的大小和多样性。在这里,我们评估了在慢性感染 1 年后才开始接受 ART 的感染 SHIV 的恒河猴,TLR7 激动剂维斯塔莫德联合 bNAb PGT121(以人 IgG1、效应增强 IgG1 或抗 CD3 双特异性抗体的形式)是否会延迟或预防停止 ART 后病毒反弹。我们发现,所有 3 种抗体形式与维斯塔莫德联合使用都能够阻止一部分动物在停止 ART 后病毒反弹。这些数据表明,TLR7 激动剂联合抗体可能是实现人类长期无 ART 的 HIV 缓解的一种有前途的策略。