Division of Virology, Department of Microbiology and Immunology, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.
National Reference Laboratory, STD AIDS Cooperative Central Laboratory, San Lazaro Hospital, Manila 1003, Metro Manila, Philippines.
Int J Mol Sci. 2022 Dec 6;23(23):15380. doi: 10.3390/ijms232315380.
It has been considered that reduced susceptibility to antiretroviral drugs is influenced by drug adherence, drug tolerance and drug-resistance-related mutations in the HIV genome. In the present study, we assessed the intrinsic high viral growth capability as a potential viral factor that may influence their susceptibility to antiretroviral drugs using an in vitro model. Phytohemagglutinin-activated peripheral blood mononuclear cells (1.5 × 10 cells) were infected with HIV isolates (10 copies/mL). The culture was carried out at different concentrations (0.001-20 μM) of 13 synthetic antiretroviral compounds (six nucleoside/nucleotide reverse transcriptase inhibitors, one non-nucleoside reverse transcriptase inhibitor, four integrase inhibitors, and two protease inhibitors), and HIV production was assessed using HIV-RNA copies in culture. The 90% inhibitory concentration (IC) and pharmacokinetics of an antiretroviral agent were used as parameters to determine the reduced antiretroviral drug susceptibility of HIV isolates with high growth capability to synthetic antiretroviral compounds. The high growth capability of HIV isolates without any known drug resistance-related mutation affected their susceptibility to tenofovir (IC = 2.05 ± 0.40 μM), lamivudine (IC = 6.83 ± 3.96 μM), emtricitabine (IC = 0.68 ± 0.37 μM), and efavirenz (IC = 3.65 ± 0.77 μM). These antiretroviral drugs showed IC values close to or above the maximum plasma concentration against HIV isolates with high growth capability without any known drug resistance-related mutation. Our results may contribute to the development of effective strategies to tailor and individualize antiretroviral therapy in patients harboring HIV isolates with high growth capability.
人们认为，抗逆转录病毒药物的敏感性降低与药物依从性、药物耐受性以及 HIV 基因组中与耐药性相关的突变有关。在本研究中，我们使用体外模型评估了内在的高病毒生长能力作为一种潜在的病毒因素，该因素可能影响它们对抗逆转录病毒药物的敏感性。用植物血球凝集素激活外周血单核细胞（1.5×10 个细胞）感染 HIV 分离株（10 拷贝/mL）。在不同浓度（0.001-20 μM）下进行培养，浓度分别为 13 种合成抗逆转录病毒化合物（6 种核苷/核苷酸逆转录酶抑制剂、1 种非核苷逆转录酶抑制剂、4 种整合酶抑制剂和 2 种蛋白酶抑制剂），并用培养物中的 HIV-RNA 拷贝评估 HIV 的产生。90%抑制浓度（IC）和抗病毒药物的药代动力学被用作参数，以确定高生长能力的 HIV 分离株对合成抗逆转录病毒化合物的抗逆转录病毒药物敏感性降低情况。没有任何已知与耐药性相关突变的 HIV 分离株的高生长能力影响了它们对替诺福韦（IC = 2.05 ± 0.40 μM）、拉米夫定（IC = 6.83 ± 3.96 μM）、恩曲他滨（IC = 0.68 ± 0.37 μM）和依非韦伦（IC = 3.65 ± 0.77 μM）的敏感性。这些抗病毒药物对高生长能力的 HIV 分离株的 IC 值接近或高于针对具有高生长能力且无任何已知耐药相关突变的 HIV 分离株的最大血浆浓度。我们的研究结果可能有助于制定有效的策略，以针对携带高生长能力 HIV 分离株的患者制定和个体化抗逆转录病毒治疗方案。
