title: Hepatitis C Virus (HCV) NS3 sequence diversity and antiviral resistance-associated variant frequency in HCV/HIV coinfection.
abstract: HIV coinfection accelerates disease progression in chronic hepatitis C and reduces sustained antiviral responses (SVR) to interferon-based therapy. New direct-acting antivirals (DAAs) promise higher SVR rates, but the selection of preexisting resistance-associated variants (RAVs) may lead to virologic breakthrough or relapse. Thus, pretreatment frequencies of RAVs are likely determinants of treatment outcome but typically are below levels at which the viral sequence can be accurately resolved. Moreover, it is not known how HIV coinfection influences RAV frequency. We adopted an accurate high-throughput sequencing strategy to compare nucleotide diversity in HCV NS3 protease-coding sequences in 20 monoinfected and 20 coinfected subjects with well-controlled HIV infection. Differences in mean pairwise nucleotide diversity (π), Tajima's D statistic, and Shannon entropy index suggested that the genetic diversity of HCV is reduced in coinfection. Among coinfected subjects, diversity correlated positively with increases in CD4(+) T cells on antiretroviral therapy, suggesting T cell responses are important determinants of diversity. At a median sequencing depth of 0.084%, preexisting RAVs were readily identified. Q80K, which negatively impacts clinical responses to simeprevir, was encoded by more than 99% of viral RNAs in 17 of the 40 subjects. RAVs other than Q80K were identified in 39 of 40 subjects, mostly at frequencies near 0.1%. RAV frequency did not differ significantly between monoinfected and coinfected subjects. We conclude that HCV genetic diversity is reduced in patients with well-controlled HIV infection, likely reflecting impaired T cell immunity. However, RAV frequency is not increased and should not adversely influence the outcome of DAA therapy.
authors.affiliation: Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Cassandra B
authors.initials: CB
authors.lastname: Jabara
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Hu
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Mollan
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Williford
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Prema
authors.initials: P
authors.lastname: Menezes
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Eron
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Fried
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Biostatistics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Department of Biology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Carolina Center for Genome Sciences, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Corbin D
authors.initials: CD
authors.lastname: Jones
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Department of Biochemistry and Biophysics, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Swanstrom
authors.affiliation: UNC Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Division of Infectious Diseases, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA smlemon@med.unc.edu.
authors.forename: Stanley M
authors.initials: SM
authors.lastname: Lemon
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D060085:Coinfection / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017361:Viral Nonstructural Proteins / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins
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