A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir

Author(s)

Fernandes Campos, Guilherme Rodrigues ^[1] ; Ward, Joseph ^{[2, 3]} ; Chen, Shucheng ^{[2, 3]} ; Bittar, Cintia ^[1] ; Vilela Rodrigues, Joao Paulo ^[4] ; Candolo Martinelli, Ana de Lourdes ^[5] ; Souza, Fernanda Fernandes ^[5] ; Leira Pereira, Leonardo Regis ^{[2, 3]} ; Rahal, Paula ^[1] ; Harris, Mark ^{[2, 3]}

Affiliation

^[1] Sao Paulo State Univ, Inst Biosci Languages & Exact Sci, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

^[2] Univ Leeds, Fac Biol Sci, Sch Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire - England

^[3] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire - England

^[4] Univ Sao Paulo, Ribeirao Preto Sch Med, BR-14049900 Ribeirao Preto, SP - Brazil

^[5] Univ Sao Paulo, Ribeirao Preto Fac Pharmaceut Sci, BR-14040903 Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF GENERAL VIROLOGY; v. 102, n. 1 2021.
• Web of Science Citations: 0

Abstract

Hepatitis C virus (HCV) genotype 3 presents a high level of both baseline and acquired resistance to direct-acting antivirals (DAAs), particularly those targeting the NS5A protein. To understand this resistance we studied a cohort of Brazilian patients treated with the NS5A DAA, daclatasvir and the nucleoside analogue, sofosbuvir. We observed a novel substitution at NS5A amino acid residue 98 {[}serine to glycine (S98G)] in patients who relapsed post-treatment. The effect of this substitution on both replication fitness and resistance to DAAs was evaluated using two genotype 3 subgenomic replicons. S98G had a modest effect on replication, but in combination with the previously characterized resistance-associated substitution (RAS), Y93H, resulted in a significant increase in daclatasvir resistance. This result suggests that combinations of substitutions may drive a high level of DAA resistance and provide some clues to the mechanism of action of the NS5A-targeting DAAs. (AU)

• FAPESP's process: 18/04678-5 - Analysis of Hepatitis C virus genotype 3 resistance to direct acting antivirals
• Grantee: Guilherme Rodrigues Fernandes Campos
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 16/03807-0 - Study of resistance mutations to treatment with Directly Acting antivirals in patients infected with hepatitis C virus genotype 3
• Grantee: Guilherme Rodrigues Fernandes Campos
• Support Opportunities: Scholarships in Brazil - Doctorate