Laboratory of Retroviral Biochemistry, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary.
Viruses. 2024 Oct 13;16(10):1607. doi: 10.3390/v16101607.
Retroviruses perpetuate their survival by incorporating a copy of their genome into the host cell, a critical step catalyzed by the virally encoded integrase. The viral capsid plays an important role during the viral life cycle, including nuclear importation in the case of lentiviruses and integration targeting events; hence, targeting the integrase and the viral capsid is a favorable therapeutic strategy. While integrase strand transfer inhibitors (INSTIs) are recommended as first-line regimens given their high efficacy and tolerability, lenacapavir is the first capsid inhibitor and the newest addition to the HIV treatment arsenal. These inhibitors are however designed for treatment of HIV-1 infection, and their efficacy against HIV-2 remains widely understudied and inconclusive, supported only by a few limited phenotypic susceptibility studies. We therefore carried out inhibition profiling of a panel of second-generation INSTIs and lenacapavir against HIV-2 in cell culture, utilizing pseudovirion inhibition profiling assays. Our results show that the tested INSTIs and lenacapavir exerted excellent efficacy against ROD-based HIV-2 integrase. We further evaluated the efficacy of raltegravir and other INSTIs against different variants of SARS-CoV-2; however, contrary to previous in silico findings, the inhibitors did not demonstrate significant antiviral activity.
逆转录病毒通过将其基因组的一个副本整合到宿主细胞中来维持其生存，这是一个由病毒编码的整合酶催化的关键步骤。病毒衣壳在病毒生命周期中起着重要作用，包括慢病毒的核导入和整合靶向事件；因此，靶向整合酶和病毒衣壳是一种有利的治疗策略。虽然整合酶链转移抑制剂（INSTIs）因其高效性和耐受性而被推荐作为一线治疗方案，但 lenacapavir 是第一种衣壳抑制剂，也是 HIV 治疗武器库中的最新成员。然而，这些抑制剂是为治疗 HIV-1 感染而设计的，它们对 HIV-2 的疗效仍广泛研究不足且尚无定论，仅得到少数有限的表型敏感性研究的支持。因此，我们利用假病毒抑制分析检测试剂盒，在细胞培养中对一组第二代 INSTIs 和 lenacapavir 对 HIV-2 的抑制作用进行了分析。我们的结果表明，测试的 INSTIs 和 lenacapavir 对基于 ROD 的 HIV-2 整合酶表现出优异的疗效。我们进一步评估了 raltegravir 和其他 INSTIs 对不同 SARS-CoV-2 变体的疗效；然而，与之前的计算机模拟结果相反，这些抑制剂并没有表现出显著的抗病毒活性。
