Interplay of Amino Acid Residues at Positions 28 and 31 in NS5A Defines Resistance Pathways in HCV GT2.
Interplay of Amino Acid Residues at Positions 28 and 31 in NS5A Defines Resistance Pathways in HCV GT2.
Antimicrob Agents Chemother. 2019 Sep 16;:
Authors: Asante-Appiah E, Ingravallo P, McMonagle P, Bystol K, Xia E, Curry S, Qiu P, Black S, Chase R, Liu R, Lahser F
Abstract
Hepatitis C virus (HCV) genotype (GT) 2 represents approximately 9% of all viral infections globally. While treatment outcomes for GT2-infected patients have improved substantially with direct-acting antiviral agents (DAAs) compared to interferon-α, the presence of polymorphisms in NS5A can impact efficacy of NS5A inhibitor-containing regimens. Thus, pathways of NS5A resistance were explored in GT2 subtypes using elbasvir, an NS5A inhibitor with broad genotype activity. Resistance selection studies, resistance analysis in NS5A-inhibitor treated virologic failures, antiviral activities in replicons bearing a panel of GT2 subtype sequences and amino acid substitutions introduced by site-directed mutagenesis were performed to define determinants of inhibitor susceptibility. Elbasvir showed differential antiviral activity in replicons bearing GT2 sequences. The EC50 values for replicons bearing reference NS5A sequences for GT2a and GT2b were 0.003 and 3.4 nanomolar (nM) respectively. Studies with recombinant replicons demonstrated crosstalk between amino acid positions 28 and 31. The combination of phenylalanine and methionine at positions 28 and 31 respectively, co...
Source: Antimicrobial Agents and Chemotherapy - Category: Microbiology Authors: Asante-Appiah E, Ingravallo P, McMonagle P, Bystol K, Xia E, Curry S, Qiu P, Black S, Chase R, Liu R, Lahser F Tags: Antimicrob Agents Chemother Source Type: research
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