Byun Hyeonah, Papathanasopoulos Maria Antonia, Steegen Kim, Basson Adriaan Erasmus
HIV Pathogenesis Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa.
National Priority Programme, National Health Laboratory Service, Johannesburg 2192, South Africa.
Viruses. 2024 Dec 6;16(12):1888. doi: 10.3390/v16121888.
Islatravir (ISL) is the first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTtI) with novel modes of action. Data on ISL resistance are currently limited, particularly to HIV-1 non-B subtypes. This study aimed to assess prevalent nucleos(t)ide reverse transcriptase inhibitor (NRTI)-resistant mutations in HIV-1 subtype C for their phenotypic resistance to ISL. Prevalent single and combinations of NRTI-resistant mutations were selected from a routine HIV-1 genotypic drug resistance testing database and introduced into HIV-1 subtype C-like pseudoviruses, which were then tested for ISL susceptibility. Single NRTI-resistant mutations were susceptible or showed only a low level of resistance to ISL. This included thymidine analogue mutations (TAMs, i.e., M41L, D67N, K70R, T215FY, and K219EQ) and non-TAMs (i.e., A62V, K65R, K70ET, L74IV, A114S, Y115F, and M184V). Combinations of M184V with one or more additional NRTI-resistant mutations generally displayed reduced ISL susceptibilities. This was more prominent for combinations that included M184V+TAMs, and particularly M184V+TAM-2 mutations. Combinations that included M184V+K65R did not impact significantly on ISL susceptibility. Our study suggests that ISL would be effective in treating people living with HIV (PLWH) failing tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or TDF/emtricitabine (FTC)-containing regimens, but would be less effective in PLH failing zidovudine (AZT) with 3TC or FTC-containing regimens.
依斯拉曲韦（ISL）是首个具有新型作用模式的核苷类逆转录酶易位抑制剂（NRTtI）。目前关于ISL耐药性的数据有限，尤其是针对HIV-1非B亚型的情况。本研究旨在评估HIV-1 C亚型中普遍存在的核苷（酸）类逆转录酶抑制剂（NRTI）耐药突变对ISL的表型耐药性。从常规HIV-1基因型耐药性检测数据库中选取普遍存在的单一及组合NRTI耐药突变，并将其引入HIV-1 C亚型样假病毒中，然后检测这些假病毒对ISL的敏感性。单一NRTI耐药突变对ISL敏感或仅表现出低水平耐药。这包括胸苷类似物突变（TAMs，即M41L、D67N、K70R、T215FY和K219EQ）和非TAMs（即A62V、K65R、K70ET、L74IV、A114S、Y115F和M184V）。M184V与一种或多种其他NRTI耐药突变的组合通常表现出对ISL敏感性降低。这在包括M184V+TAMs，尤其是M184V+TAM-2突变的组合中更为突出。包括M184V+K65R的组合对ISL敏感性没有显著影响。我们的研究表明，ISL对使用富马酸替诺福韦二吡呋酯（TDF）/拉米夫定（3TC）或含TDF/恩曲他滨（FTC）方案治疗失败的HIV感染者（PLWH）有效，但对使用齐多夫定（AZT）联合3TC或含FTC方案治疗失败的PLH效果较差。
