Lenacapavir (LEN; GS-6207) is a potent first-in-class inhibitor of HIV-1 capsid with long-acting properties and the potential for subcutaneous dosing every 3 months or longer. In the clinic, a single subcutaneous LEN injection (20 mg to 750 mg) in people with HIV (PWH) induced a strong antiviral response, with a >2.3 mean log₁₀ decrease in HIV-1 RNA at day 10. HIV-1 Gag mutations near protease (PR) cleavage sites have emerged with the use of protease inhibitors (PIs). Here, we have characterized the activity of LEN in mutants with Gag cleavage site mutations (GCSMs) and mutants resistant to other drug classes. HIV mutations were inserted into the pXXLAI clone, and the resulting mutants (n = 70) were evaluated using a 5-day antiviral assay. LEN EC₅₀ fold change versus the wild type ranged from 0.4 to 1.9 in these mutants, similar to that for the control drug. In contrast, reduced susceptibility to PIs and maturation inhibitors (MIs) was observed. Testing of isolates with resistance against the 4 main classes of drugs (n = 40) indicated wild-type susceptibility to LEN (fold change ranging from 0.3 to 1.1), while reduced susceptibility was observed for control drugs. HIV GCSMs did not impact the activity of LEN, while some conferred resistance to MIs and PIs. Similarly, LEN activity was not affected by naturally occurring variations in HIV Gag, in contrast to the reduced susceptibility observed for MIs. Finally, the activity of LEN was not affected by the presence of resistance mutations to the 4 main antiretroviral (ARV) drug classes. These data support the evaluation of LEN in PWH with multiclass resistance.

中文翻译：

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在 HIV Gag 裂解位点突变体和对现有药物类别具有抗性的分离株中不存在 Lenacapavir (GS-6207) 表型抗性

Lenacapavir (LEN; GS-6207) 是一种有效的一流 HIV-1 衣壳抑制剂，具有长效特性，并且有可能每 3 个月或更长时间进行一次皮下给药。在临床中，对 HIV 感染者 (PWH) 进行单次皮下注射 LEN（20 毫克至 750 毫克）可诱导强烈的抗病毒反应，第 10 天 HIV-1 RNA 的平均 log ₁₀降低>2.3 。 HIV-1 Gag随着蛋白酶抑制剂 (PI) 的使用，蛋白酶 (PR) 裂解位点附近的突变已经出现。在这里，我们描述了 LEN 在具有 Gag 切割位点突变 (GCSM) 的突变体和对其他药物类别具有抗性的突变体中的活性。将 HIV 突变插入 pXXLAI 克隆，并使用 5 天抗病毒试验评估所得突变体 ( n = 70)。莱恩EC ₅₀在这些突变体中，相对于野生型的倍数变化范围从 0.4 到 1.9，类似于对照药物的变化。相比之下，观察到对 PI 和成熟抑制剂 (MI) 的敏感性降低。检测对 4 类主要药物具有耐药性的分离株 ( n= 40) 表明野生型对 LEN 的敏感性（倍数变化范围从 0.3 到 1.1），而对照药物的敏感性降低。HIV GCSMs 不影响 LEN 的活性，而一些赋予对 MIs 和 PIs 的抗性。同样，与观察到的 MI 易感性降低相反，LEN 活性不受 HIV Gag 中自然发生的变化的影响。最后，LEN 的活性不受对 4 种主要抗逆转录病毒 (ARV) 药物类别的抗性突变的影响。这些数据支持对具有多类耐药性的 PWH 中的 LEN 进行评估。