Rodríguez-López Elliott R, López Pablo, Rodríguez Yadira, Sánchez Raphael, Acevedo Van-Sergei, Encarnación Jarline, Tirado Grissell, Ortiz-Sánchez Carmen, Mesplède Thibault, Rivera-Amill Vanessa
RCMI Center for Research Resources, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico.
Viroscience Department, Erasmus University Medical Center, Rotterdam, The Netherlands.
AIDS Res Hum Retroviruses. 2025 Jan;41(1):43-54. doi: 10.1089/AID.2023.0128. Epub 2024 Aug 20.
The recently Food and Drug Administration (FDA)-approved cabotegravir (CAB) has demonstrated efficacy as an antiretroviral agent for HIV treatment and prevention, becoming an important tool to stop the epidemic in the United States of America (USA). However, the effectiveness of CAB can be compromised by the presence of specific integrase natural polymorphisms, including T97A, L74M, M50I, S119P, and E157Q, particularly when coupled with the primary drug-resistance mutations G140S and Q148H. CAB's recent approval as a pre-exposure prophylaxis (PrEP) may increase the number of individuals taking CAB, which, at the same time, could increase the number of epidemiological implications. In this context, where resistance mutations, natural polymorphisms, and the lack of drug-susceptibility studies prevail, it becomes imperative to comprehensively investigate concerns related to the use of CAB. We used molecular and cell-based assays to assess the impact of T218I and T218S in the context of major resistance mutations G140S/Q148H on infectivity, integration, and resistance to CAB. Our findings revealed that T218I and T218S, either individually or in combination with G140S/Q148H, did not significantly affect infectivity, integration, or resistance to CAB. Notably, these polymorphisms also exhibited neutrality concerning other widely used integrase inhibitors, namely raltegravir, elvitegravir, and dolutegravir. Thus, our study suggests that the T218I and T218S natural polymorphisms are unlikely to undermine the effectiveness of CAB as a treatment and PrEP strategy.
美国食品药品监督管理局（FDA）最近批准的卡博特韦（CAB）已证明作为一种抗逆转录病毒药物在治疗和预防HIV方面具有疗效，成为美国阻止该流行病传播的重要工具。然而，特定整合酶自然多态性的存在，包括T97A、L74M、M50I、S119P和E157Q，可能会损害CAB的有效性，特别是当与主要耐药突变G140S和Q148H同时出现时。CAB最近被批准用于暴露前预防（PrEP）可能会增加服用CAB的人数，与此同时，这可能会增加流行病学方面的影响。在这种存在耐药突变、自然多态性且缺乏药物敏感性研究的背景下，全面调查与使用CAB相关的问题变得势在必行。我们使用基于分子和细胞的检测方法，在主要耐药突变G140S/Q148H的背景下评估T218I和T218S对感染性、整合以及对CAB耐药性的影响。我们的研究结果表明，T218I和T218S单独或与G140S/Q148H联合使用时，对感染性、整合或对CAB的耐药性均无显著影响。值得注意的是，这些多态性对其他广泛使用的整合酶抑制剂，即拉替拉韦、埃替拉韦和度鲁特韦也表现出中性。因此，我们的研究表明，T218I和T218S自然多态性不太可能削弱CAB作为治疗和PrEP策略的有效性。
