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Open AccessArticle

Factors Influencing the Prevalence of Resistance-Associated Substitutions in NS5A Protein in Treatment-Naive Patients with Chronic Hepatitis C

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Russian Medical Academy of Continuous Professional Education, 125993 Moscow, Russia
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Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia
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Chumakov Federal Scientific Center for Research and Development of Immune-and-Biological Products of Russian Academy of Sciences, 108819 Moscow, Russia
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N.V. Sklifosovsky Research Institute for Emergency Medicine, 129090 Moscow, Russia
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Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institute, 17165 Solna, Sweden
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Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, San Martín CP1650, Argentina
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Department of Bio and Health Informatics, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark
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NF Gamaleja Research Center of Epidemiology and Microbiology, 123098 Moscow, Russia
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Research Department, Riga Stradins University, LV-1007 Riga, Latvia
*
Authors to whom correspondence should be addressed.
Biomedicines 2020, 8(4), 80; https://doi.org/10.3390/biomedicines8040080
Received: 6 February 2020 / Revised: 24 March 2020 / Accepted: 5 April 2020 / Published: 7 April 2020
(This article belongs to the Section Virology, Vaccines and Viral Vectors)
Direct-acting antivirals (DAAs) revolutionized treatment of hepatitis C virus (HCV) infection. Resistance-associated substitutions (RASs) present at the baseline impair response to DAA due to rapid selection of resistant HCV strains. NS5A is indispensable target of the current DAA treatment regimens. We evaluated prevalence of RASs in NS5A in DAA-naïve patients infected with HCV 1a (n = 19), 1b (n = 93), and 3a (n = 90) before systematic DAA application in the territory of the Russian Federation. Total proportion of strains carrying at least one RAS constituted 35.1% (71/202). In HCV 1a we detected only M28V (57.9%) attributed to a founder effect. Common RASs in HCV 1b were R30Q (7.5%), L31M (5.4%), P58S (4.4%), and Y93H (5.4%); in HCV 3a, A30S (31.0%), A30K (5.7%), S62L (8.9%), and Y93H (2.2%). Prevalence of RASs in NS5A of HCV 1b and 3a was similar to that worldwide, including countries practicing massive DAA application, i.e., it was not related to treatment. NS5A with and without RASs exhibited different co-variance networks, which could be attributed to the necessity to preserve viral fitness. Majority of RASs were localized in polymorphic regions subjected to immune pressure, with selected substitutions allowing immune escape. Altogether, this explains high prevalence of RAS in NS5A and low barrier for their appearance in DAA-inexperienced population. View Full-Text
Keywords: hepatitis C virus (HCV); NS5A; resistance-associated substitutions; direct-acting antivirals; amino acid covariance; immune escape hepatitis C virus (HCV); NS5A; resistance-associated substitutions; direct-acting antivirals; amino acid covariance; immune escape
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Kyuregyan, K.K.; Kichatova, V.S.; Karlsen, A.A.; Isaeva, O.V.; Solonin, S.A.; Petkov, S.; Nielsen, M.; Isaguliants, M.G.; Mikhailov, M.I. Factors Influencing the Prevalence of Resistance-Associated Substitutions in NS5A Protein in Treatment-Naive Patients with Chronic Hepatitis C. Biomedicines 2020, 8, 80.

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