Hikichi Yuta, Burdick Ryan C, Patro Sean C, Ding Si-Yuan, Luke Brian T, Clark Erin D, Ablan Sherimay D, Wu Xiaolin, Pathak Vinay K, Freed Eric O
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Viral Mutation Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
Sci Adv. 2025 Sep 12;11(37):eadz8980. doi: 10.1126/sciadv.adz8980.
Persons with HIV (PWH) receiving integrase (IN) strand transfer inhibitors (INSTIs) have been reported to experience virologic failure (VF) in the absence of resistance mutations in IN. We previously reported that mutations in the viral nucleocapsid (NC) are selected in the presence of the INSTI dolutegravir (DTG). Here, we show that these NC mutations accelerate the kinetics of viral DNA integration, suggesting that they limit the window of time available for INSTIs to block viral DNA integration. We find that in primary peripheral blood mononuclear cells, HIV-1 acquires mutations in the viral envelope glycoprotein, NC, and occasionally IN during selection for INSTI resistance. Notably, the selected NC and IN mutations act in concert to reduce the susceptibility of the virus to INSTIs. These results provide insights into the mechanism by which HIV-1 escapes the inhibitory activity of INSTIs and underscore the importance of genotypic analysis outside IN in PWH experiencing VF on INSTI-containing drug regimens.
据报道，接受整合酶（IN）链转移抑制剂（INSTIs）治疗的艾滋病毒感染者（PWH）在整合酶不存在耐药突变的情况下会出现病毒学失败（VF）。我们之前报道过，在INSTI度鲁特韦（DTG）存在的情况下，病毒核衣壳（NC）会发生突变。在此，我们表明这些NC突变会加速病毒DNA整合的动力学，这表明它们限制了INSTIs阻断病毒DNA整合的可用时间窗口。我们发现，在原代外周血单核细胞中，在选择INSTI耐药性的过程中，HIV-1在病毒包膜糖蛋白、NC以及偶尔在IN中获得突变。值得注意的是，所选的NC和IN突变共同作用，降低了病毒对INSTIs的敏感性。这些结果为HIV-1逃避INSTIs抑制活性的机制提供了见解，并强调了在接受含INSTI药物方案治疗且出现VF的PWH中，对整合酶以外区域进行基因型分析的重要性。
