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.

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