Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist–induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8⁺ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques.

抗逆转录病毒疗法 (ART) 可以阻止 HIV-1 复制，但无法针对长寿命的潜伏病毒库。已经评估了几种药理学化合物逆转 HIV-1 潜伏期的能力，但没有一种化合物能够明显减少潜伏的 HIV-1 储存库或影响 ART 中断后的病毒反弹。我们评估了口服选择性 Toll 样受体 7 (TLR7) 激动剂 GS-986 和 GS-9620 在感染猿猴免疫缺陷病毒 (SIV) 并接受抑制性 ART 治疗的恒河猴中诱导短暂病毒血症的能力。在最初的剂量递增研究和随后的剂量优化研究中，我们发现 TLR7 激动剂除了诱导 SIV RNA 的表达外，还激活多个先天性和适应性免疫细胞群。我们还观察到 TLR7 激动剂诱导的 SIV DNA 减少，并在离体细胞培养物中测量了治疗动物的诱导病毒。在第二项研究中，停止 ART 后，九只接受治疗的动物中有两只在 2 年多的时间内仍保持无病毒血症，即使在体内 CD8 ⁺ T 细胞耗尽后也是如此。此外，来自无病毒血症动物的细胞的过继转移不能在幼稚受体猕猴中诱导从头感染。这些发现表明，TLR7 激动剂可能有助于减少感染 SIV 的恒河猴中的病毒库。