Smith Steven J, Zhao Xue Zhi, Hughes Stephen H, Burke Terrence R
Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
Viruses. 2025 Jan 16;17(1):121. doi: 10.3390/v17010121.
Second-generation integrase strand transfer inhibitors (INSTIs) are strongly recommended for people living with HIV-1 (PLWH). The emergence of resistance to second-generation INSTIs has been infrequent and has not yet been a major issue in high-income countries. However, the delayed rollouts of these INSTIs in low- to middle-income countries during the COVID-19 pandemic combined with increased transmission of drug-resistant mutants worldwide are leading to an increase in INSTI resistance. Herein, we evaluated the antiviral potencies of our lead developmental INSTI 4d and the second-generation INSTIs dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) against a panel of IN quadruple mutants. The mutations are centered around G140S/Q148H, including positions L74, E92, and T97 combined with E138A/K/G140S/Q148H. All of the tested INSTIs lose potency against these IN quadruple mutants compared with the wild-type IN. In single-round infection assays, compound 4d retained higher antiviral potencies (EC values) than second-generation INSTIs against a subset of quadruple mutants. These findings may advance understanding of mechanisms that contribute to resistance and, in so doing, facilitate development of new INSTIs with improved antiviral profiles.
强烈推荐第二代整合酶链转移抑制剂（INSTIs）用于HIV-1感染者（PLWH）。对第二代INSTIs产生耐药性的情况并不常见，在高收入国家尚未成为一个主要问题。然而，在新冠疫情期间，这些INSTIs在低收入和中等收入国家的推广延迟，再加上全球耐药突变体传播增加，导致INSTI耐药性上升。在此，我们评估了我们正在研发的先导INSTI 4d以及第二代INSTIs度鲁特韦（DTG）、比克替韦（BIC）和卡博特韦（CAB）对一组整合酶四重突变体的抗病毒效力。这些突变集中在G140S/Q148H周围，包括L74、E92和T97位点，并与E138A/K/G140S/Q148H组合。与野生型整合酶相比，所有测试的INSTIs对这些整合酶四重突变体的效力均降低。在单轮感染试验中，化合物4d对一部分四重突变体保留了比第二代INSTIs更高的抗病毒效力（EC值）。这些发现可能会促进对耐药机制的理解，从而有助于开发具有更好抗病毒谱的新型INSTIs。
