University of Rome 'Tor Vergata', Rome, Italy.
Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), Yaoundé, Cameroon.
J Antimicrob Chemother. 2020 Jul 1;75(7):1778-1786. doi: 10.1093/jac/dkaa073.
We evaluated natural resistance to the new antiretroviral fostemsavir and its potential association with other HIV-1 gp120 polymorphisms.
A total of 1997 HIV-1 B subtype gp120 sequences from the Los Alamos HIV Database were analysed for mutation prevalence at fostemsavir resistance-associated positions and potential association with other gp120 polymorphisms. The role of each fostemsavir resistance-related position and the correlated gp120 mutations, both in protein stability and in reducing the binding affinity between antibody and/or T cell lymphocyte epitopes and the MHC molecules, was estimated.
The prevalence of fostemsavir resistance mutations was as follows: L116Q (0.05%), S375H/M/T (0.55%/1.35%/17.73%, the latter being far less relevant in determining resistance), M426L (7.56%), M434I (4.21%) and M475I (1.65%). Additionally, the M426R polymorphism had a prevalence of 16.32%. A significantly higher prevalence in X4 viruses versus R5 viruses was found only for S375M (0.69% versus 3.93%, P = 0.009) and S375T (16.60% versus 22.11%, P = 0.030). Some fostemsavirv resistance positions positively and significantly correlated with specific gp120 polymorphisms: S375T with I371V; S375M with L134W, I154V and I323T; M475I with K322A; and M426R with G167N, K192T and S195N. The topology of the dendrogram suggested the existence of three distinct clusters (bootstrap ≥0.98) involving these fostemsavir resistance mutations and gp120 polymorphisms. Interestingly, all clustered mutations are localized in class I/II-restricted T cell/antibody epitopes, suggesting a potential role in immune HIV escape.
A low prevalence of known fostemsavir resistance mutations was found in the HIV-1 B subtype. The detection of novel HIV-1 gp120 polymorphisms potentially relevant for fostemsavir resistance deserves new in-depth in vitro investigations.
评估新型抗逆转录病毒 fostemsavir 的天然耐药性及其与其他 HIV-1 gp120 多态性的潜在关联。
对来自 Los Alamos HIV 数据库的 1997 株 HIV-1 B 亚型 gp120 序列进行分析，以确定 fostemsavir 耐药相关位置的突变流行率，并确定其与其他 gp120 多态性的潜在关联。评估每个 fostemsavir 耐药相关位置及其相关 gp120 突变在蛋白质稳定性和降低抗体和/或 T 细胞淋巴细胞表位与 MHC 分子结合亲和力方面的作用。
fostemsavir 耐药突变的流行率如下：L116Q（0.05%）、S375H/M/T（0.55%/1.35%/17.73%，后者在确定耐药性方面相关性较小）、M426L（7.56%）、M434I（4.21%）和 M475I（1.65%）。此外，M426R 多态性的流行率为 16.32%。与 R5 病毒相比，X4 病毒中 S375M（0.69%对 3.93%，P=0.009）和 S375T（16.60%对 22.11%，P=0.030）的耐药突变发生率显著更高。一些 fostemsavir 耐药位置与特定的 gp120 多态性呈正相关且显著相关：S375T 与 I371V；S375M 与 L134W、I154V 和 I323T；M475I 与 K322A；M426R 与 G167N、K192T 和 S195N。树状图的拓扑结构表明，这些 fostemsavir 耐药突变和 gp120 多态性存在三个不同的簇（自举值≥0.98）。有趣的是，所有聚类突变都位于 I 类/II 类限制性 T 细胞/抗体表位，这表明它们可能在 HIV 免疫逃逸中发挥作用。
在 HIV-1 B 亚型中发现了已知 fostemsavir 耐药突变的低流行率。检测到可能与 fostemsavir 耐药相关的新型 HIV-1 gp120 多态性值得进一步深入的体外研究。
