Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA.
Nat Chem Biol. 2023 Apr;19(4):431-439. doi: 10.1038/s41589-022-01182-5. Epub 2022 Nov 10.
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.
非核苷类逆转录酶抑制剂（NNRTIs）通过诱导细胞内 HIV-1 蛋白酶活性诱导 HIV-1 感染的 CD4 T 细胞发生细胞焦亡，从而激活 CARD8 炎性小体。由于需要高浓度的 NNRTIs 才能有效清除 HIV-1 感染的细胞，因此阐明使 CARD8 炎性小体对 NNRTI 诱导的激活敏感的方法非常重要。我们表明，通过化学抑制 CARD8 的负调节剂 DPP9 可以实现这种敏化。DPP9 抑制剂 Val-boroPro（VbP）可以在没有 NNRTIs 的情况下杀死 HIV-1 感染的细胞，并与 NNRTIs 协同作用，促进体外和人源化小鼠中 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）中分离的 CD4 T 细胞中清除残余 HIV-1 的能力。我们还表明，VbP 可以部分克服 NNRTI 耐药性。这为增强 NNRTI 清除 PLWH 中 HIV-1 储存库的疗效提供了一种有前途的策略。
