Discussion: An important exception to the broad coverage of TMR is with CRF01_AE viruses, wherein envelopes routinely exhibited high IC50 values to TMR, owing to the regular presence of two key polymorphisms (S375H and M475I) in most CFR01_AE viruses.
Discussion: Within the six participants (where data were available) who encountered PDVF when co-dosed with FTR and either IBA or MVC, five participants had emergent substitutions of S375H/N, M426L, or M475I, while Individual 153, with an M426L at Screening, had no TMR-specific emergent changes but did exhibit a relatively high but unchanged IC50 at Screening and PDVF.
Week 96 Genotypic and Phenotypic Results of the Fostemsavir Phase 3 BRIGHTE Study in Heavily Treatment-Experienced Adults Living with Multidrug-Resistant HIV-1.
PMID: 35502922
2022
Antimicrobial agents and chemotherapy
Abstract: The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC).
Identification of gp120 polymorphisms in HIV-1 B subtype potentially associated with resistance to fostemsavir.
PMID: 32160290
2020
The Journal of antimicrobial chemotherapy
Abstract: RESULTS: 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%).
Gp120 substitutions at positions associated with resistance to fostemsavir in treatment-naive HIV-1-positive individuals.
PMID: 32191306
2020
The Journal of antimicrobial chemotherapy
Abstract: METHODS: 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.
Abstract: RESULTS: 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%).
Natural presence of the V179D and K103R/V179D mutations associated with resistance to nonnucleoside reverse transcriptase inhibitors in HIV-1 CRF65_cpx strains.
Introduction: reported that CRF01_AE subtype-related resistance to fostemsavir, an attachment inhibitor, appeared to be associated with the natural presence of substitutions S375H and M475I.
Impact of natural polymorphisms of HIV-1 non-group M on genotypic susceptibility to the attachment inhibitor fostemsavir.
PMID: 30032194
2018
The Journal of antimicrobial chemotherapy
Abstract: Methods: The frequency of eight substitutions associated with decreased susceptibility to fostemsavir (L116P, A204D, S375M/H, M426L, M434I, M475I and V506M), was investigated in 111 gp120 sequences from groups O (n = 100), N (n = 9) and P (n = 2).
Abstract: Results: All HIV-1 group N sequences harboured the three substitutions S375M, M426L and M434I, whereas only 1% and 10% of HIV-1 group O sequences harboured the S375H + M426L and S375H + M434I p
Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses.
Abstract: Filling this cavity with a histidine or tryptophan residue in Env with a natural serine residue at this position (S375H/W) increased the susceptibility of HIV-1-infected cells to ADCC.
Abstract: In HIV-1, substitution of large residues such as histidine or tryptophan for serine 375 (S375H/W) in the gp120 Phe 43 cavity, where Phe 43 of CD4 contacts gp120, results in the spontaneous sampling of an Env conformation closer to the CD4-bound state.
Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor.
Abstract: Additional neutralization experiments indicate that 882376 is not active against mutant pseudoviruses carrying the amino acid substitutions S375H and S375Y located in the 'Phe43 cavity' which is the major site of CD4 binding, suggesting that this compound may interfere with the interaction between gp120 and CD4.
Result: To better understand the binding site of 882376 we also investigated its inhibitory activity against pseudoviruses carrying the S37
Discussion: In fact, the substitution S375H was suggested to be responsible for the resistance of the CRF01_AE HIV-1 to a potent entry inhibitor, BMS-599793 .
Discussion: In this study we tested 882376 against two mutant pseudoviruses carrying single substitution S375H and S375Y.
HIV mutation literature information.
PMID: 
2022
AIDS (London, England)
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