Clinic of Infectious Diseases, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, Italy.
Malattie Infettive e Tropicali, Ospedale Oncologico San Giuseppe Moscati, Taranto, Italy.
J Antimicrob Chemother. 2020 Jun 1;75(6):1580-1587. doi: 10.1093/jac/dkaa034.
Fostemsavir, a novel attachment inhibitor targeting the HIV-1 gp120, has demonstrated wide in vitro activity. However, the high rate of HIV gp120 substitutions could jeopardize its efficacy. We investigated envelope (env) substitutions at positions associated with resistance to fostemsavir in patients with a new HIV-1 diagnosis according to HIV subtype and tropism.
Gp120 sequences from 409 subjects were retrospectively analysed and the presence of the L116P, A204D, S375H/M/T, M426L, M434I and M475I mutations was evaluated. Other amino acid changes at the same positions were also recorded. The variability at each amino acid position was evaluated using Shannon entropy.
The frequency of mutations was: S375T (13.2%); M426L (6.8%); M434I (2.9%); M475I (2.7%); S375H (1.0%)/M (0.8%) and L116P (0.31%). Statistically significant differences were found at positions 375 (R5/non-R5 strains and B/non-B subtypes) and 426 (B/non-B subtypes); post hoc analysis revealed that significance for position 375 was steered by S375T while for position 426 significance was governed by unusual substitutions, in particular M426R (B/non-B, P < 0.00001). The variability of env constant domains appeared to be more relevant in the non-B virus population.
In conclusion, gp120 substitutions were detected in different subtypes and in both R5 and non-R5 variants. Despite the great variability of gp120, the frequency of mutations was low overall and the predominant substitution was S375T, the role of which in reducing fostemsavir efficacy is less substantial.
福替司韦是一种新型的 HIV-1 附着抑制剂，具有广泛的体外活性。然而，HIV gp120 的高替换率可能会危及它的疗效。我们根据 HIV 亚型和嗜性，研究了新诊断为 HIV-1 的患者中与福替司韦耐药相关的包膜（env）替换。
回顾性分析了 409 例患者的 gp120 序列，评估了 L116P、A204D、S375H/M/T、M426L、M434I 和 M475I 突变的存在。还记录了同一位置的其他氨基酸变化。使用香农熵评估每个氨基酸位置的变异性。
突变的频率为：S375T（13.2%）；M426L（6.8%）；M434I（2.9%）；M475I（2.7%）；S375H（1.0%）/M（0.8%）和 L116P（0.31%）。在位置 375（R5/非 R5 株和 B/非 B 亚型）和 426（B/非 B 亚型）发现了统计学上的显著差异；事后分析表明，位置 375 的显著性由 S375T 驱动，而位置 426 的显著性由异常替换驱动，特别是 M426R（B/非 B，P<0.00001）。env 恒定区的变异性在非 B 病毒群体中似乎更为重要。
总之，在不同的亚型和 R5 和非 R5 变体中检测到了 gp120 替换。尽管 gp120 的变异性很大，但总的突变频率较低，主要的替换是 S375T，其降低福替司韦疗效的作用较小。
