Deconvoluting the Composition of Low-Frequency Hepatitis C Viral Quasispecies: Comparison of Genotypes and NS3 Resistance-Associated Variants between HCV/HIV Coinfected Hemophiliacs and HCV Monoinfected Patients in Japan

被引:14
|
作者
Ogishi, Masato [1 ]
Yotsuyanagi, Hiroshi [1 ]
Tsutsumi, Takeya [1 ]
Gatanaga, Hiroyuki [2 ]
Ode, Hirotaka [3 ]
Sugiura, Wataru [3 ]
Moriya, Kyoji [1 ]
Oka, Shinichi [2 ]
Kimura, Satoshi [4 ,5 ]
Koike, Kazuhiko [1 ]
机构
[1] Univ Tokyo, Grad Sch Med, Dept Internal Med, Bunkyo Ku, Tokyo, Japan
[2] Natl Ctr Global Hlth & Med, AIDS Clin Ctr, Shinjuku Ku, Tokyo, Japan
[3] Nagoya Med Ctr, Clin Res Ctr, Dept Infect Dis & Immunol, Nagoya, Aichi, Japan
[4] Tokyo Teishin Hosp, Tokyo, Japan
[5] Tokyo Hlth Care Univ, Tokyo, Japan
来源
PLOS ONE | 2015年 / 10卷 / 03期
关键词
HUMAN-IMMUNODEFICIENCY-VIRUS; TREATMENT-NAIVE PATIENTS; ACTING ANTIVIRAL AGENTS; PEGYLATED INTERFERON; GENETIC DIVERSITY; DNA-POLYMERASE; HIV-1; PROTEASE; INFECTION; SIMEPREVIR; PREVALENCE;
D O I
10.1371/journal.pone.0119145
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Pre-existing low-frequency resistance-associated variants (RAVs) may jeopardize successful sustained virological responses (SVR) to HCV treatment with direct-acting antivirals (DAAs). However, the potential impact of low-frequency (similar to 0.1%) mutations, concatenated mutations (haplotypes), and their association with genotypes (Gts) on the treatment outcome has not yet been elucidated, most probably owing to the difficulty in detecting pre-existing minor haplotypes with sufficient length and accuracy. Herein, we characterize a methodological framework based on Illumina MiSeq next-generation sequencing (NGS) coupled with bioinformatics of quasispecies reconstruction (QSR) to realize highly accurate variant calling and genotype-haplotype detection. The core-to-NS3 protease coding sequences in 10 HCV monoinfected patients, 5 of whom had a history of blood transfusion, and 11 HCV/HIV coinfected patients with hemophilia, were studied. Simulation experiments showed that, for minor variants constituting more than 1%, our framework achieved a positive predictive value (PPV) of 100% and sensitivities of 91.7-100% for genotyping and 80.6% for RAV screening. Genotyping analysis indicated the prevalence of dominant Gt1a infection in coinfected patients (6/11 vs 0/10, p = 0.01). For clinical samples, minor genotype overlapping infection was prevalent in HCV/HIV coinfected hemophiliacs (10/11) and patients who experienced whole-blood transfusion (4/5) but none in patients without exposure to blood (0/5). As for RAV screening, the Q80K/R and S122K/R variants were particularly prevalent among minor RAVs observed, detected in 12/21 and 6/21 cases, respectively. Q80K was detected only in coinfected patients, whereas Q80R was predominantly detected in monoinfected patients (1/11 vs 7/10, p < 0.01). Multivariate interdependence analysis revealed the previously unrecognized prevalence of Gt1b-Q80K, in HCV/HIV coinfected hemophiliacs [Odds ratio = 13.4 (3.48-51.9), p < 0.01]. Our study revealed the distinct characteristics of viral quasispecies between the subgroups specified above and the feasibility of NGS and QSR-based genetic deconvolution of pre-existing minor Gts, RAVs, and their interrelationships.
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