Non-nucleoside reverse transcriptase inhibitors (NNRTIs) induce pyroptosis of HIV-1-infected CD4⁺ T cells through induction of intracellular HIV-1 protease activity, which activates the CARD8 inflammasome. Because high concentrations of NNRTIs are required for efficient elimination of HIV-1-infected cells, it is important to elucidate ways to sensitize the CARD8 inflammasome to NNRTI-induced activation. We show that this sensitization can be achieved through chemical inhibition of the CARD8 negative regulator DPP9. The DPP9 inhibitor Val-boroPro (VbP) can kill HIV-1-infected cells without the presence of NNRTIs and act synergistically with NNRTIs to promote clearance of HIV-1-infected cells in vitro and in humanized mice. More importantly, VbP is able to enhance clearance of residual HIV-1 in CD4⁺ T cells isolated from people living with HIV (PLWH). We also show that VbP can partially overcome NNRTI resistance. This offers a promising strategy for enhancing NNRTI efficacy in the elimination of HIV-1 reservoirs in PLWH.

非核苷逆转录酶抑制剂 (NNRTI)通过诱导细胞内 HIV-1 蛋白酶活性（激活 CARD8 炎性体），诱导 HIV-1 感染的CD4 ^{+ T 细胞焦亡。}由于有效消除 HIV-1 感染的细胞需要高浓度的 NNRTI，因此阐明使 CARD8 炎性体对 NNRTI 诱导的激活敏感的方法非常重要。我们证明这种敏化可以通过 CARD8 负调节因子 DPP9 的化学抑制来实现。DPP9 抑制剂 Val-boroPro (VbP) 可以在不存在 NNRTI 的情况下杀死 HIV-1 感染的细胞，并与 NNRTI 协同作用，在体外和人源化小鼠中促进 HIV-1 感染细胞的清除。更重要的是，VbP 能够增强从 HIV 感染者 (PLWH) 中分离出的CD4 ^{+ T 细胞中残留 HIV-1 的清除率。}我们还表明，VbP 可以部分克服 NNRTI 耐药性。这为增强 NNRTI 消除 PLWH 中 HIV-1 病毒库的功效提供了一种有前景的策略。