Hui Li

University of Washington Seattle, Seattle, WA, United States

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Publications (6)22.23 Total impact

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    ABSTRACT: Secreted infectious particles generated by the genotype 2a JFH-1 hepatitis C virus infectious clone are resistant to acidic pH, whereas intracellular virions remain acid-labile. Thus, JFH-1 particles are thought to undergo pH maturation as they are secreted from the cell. Here, we demonstrate that both infectious intracellular and secreted genotype 1a (H77)/JFH-1 chimaeric particles display enhanced acid sensitivity compared with JFH-1, although pH maturation still occurs upon release. Introduction of p7 sequences from genotype 1a infected HCV patients into the H77/JFH-1 background yielded variable effects on infectious particle production and sensitivity to small molecule inhibitors. However, two selected patient p7 sequences increased the acid stability of secreted, but not intracellular H77/JFH-1 particles, suggesting that p7 directly influences particle pH maturation via an as yet undefined mechanism. We propose that HCV particles vary in acid stability, and that this may be dictated by variations in both canonical structural proteins and p7.
    Virology 01/2014; 448C:117-124. · 3.35 Impact Factor
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    ABSTRACT: The present study describes natural genetic heterogeneity of hepatitis C virus (HCV) p7 protein, the ion channel that plays a critical role in assembly and release of HCV, within 299 variants isolated from serum specimens of 27 chronically infected patients, 12 of whom with human immunodeficiency virus (HIV) co-infection. Liver fibrosis stage was inversely correlated with p7 synonymous substitutions (dS) (p=0.033), and indices of p7 genetic diversity were significantly higher in HIV-negative subjects compared to HIV-positive subjects (dS, p=0.005; non-synonymous substitutions (dN), p=0.002; dN/dS ratio, p=0.024; amino acid distances, p=0.007). Six p7 genes with naturally occurring unique amino acid variations were selected for in vitro study. The variants demonstrated diversified functional heterogeneity in vitro, with one variant from a subject with severe liver disease displaying hyperactive ion channel function, as well as other variants presenting altered pH-activated channel gating activities.
    Virology 12/2011; 423(1):30-7. · 3.35 Impact Factor
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    ABSTRACT: Infection with hepatitis C virus (HCV) is one of the leading causes of chronic hepatitis, liver cirrhosis and end-stage liver disease worldwide. The genetics of HCV infection in humans and the disease course of chronic hepatitis C are both remarkably variable. Although the response to interferon treatment is largely dependent on HCV genotypes, whether or not a relationship exists between HCV genome variability and clinical course of hepatitis C disease still remains unknown. To more thoroughly understand HCV genome evolution over time in association with disease course, near genome-wide HCV genomes present in 9 chronically infected participants over 83 total study years were sequenced. Overall, within HCV genomes, the number of synonymous substitutions per synonymous site (d(S)) significantly exceeded the number of non-synonymous substitutions per site (d(N)). Although both d(S) and d(N) significantly increased with duration of chronic infection, there was a highly significant decrease in d(N)/d(S) ratio in HCV genomes over time. These results indicate that purifying selection acted to conserve viral protein structure despite persistence of high level of nucleotide mutagenesis inherent to HCV replication. Based on liver biopsy fibrosis scores, HCV genomes from participants with advanced fibrosis had significantly greater d(S) values and lower d(N)/d(S) ratios compared to participants with mild liver disease. Over time, viral genomes from participants with mild disease had significantly greater annual changes in d(N), along with higher d(N)/d(S) ratios, compared to participants with advanced fibrosis. Yearly amino acid variations in the HCV p7, NS2, NS3 and NS5B genes were all significantly lower in participants with severe versus mild disease, suggesting possible pathogenic importance of protein structural conservation for these viral gene products.
    PLoS ONE 01/2011; 6(5):e19562. · 3.73 Impact Factor
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    ABSTRACT: Approximately 20% of patients receiving liver transplants for end-stage hepatitis C rapidly develop severe allograph fibrosis within the first 24 months after transplant. Hepatitis C virus (HCV) variants were studied in 56 genotype-1-infected subjects with end-stage hepatitis C disease at the time before and 12 months after liver transplant, and post-transplant outcome was followed with serial liver biopsies. In 15 cases, pre-transplant HCV genetic diversity was studied in detail in liver (n=15), serum (n=15), peripheral blood mononuclear cells (n=13), and perihepatic lymph nodes (n=10). Our results revealed that pre-transplant HCV genetic diversity predicted the histological outcome of recurrent hepatitis C disease after transplant. Mild disease recurrence after transplant was significantly associated with higher genetic diversity and greater diversity changes between the pre- and post-transplant time points (p=0.004). Meanwhile, pre-transplant genetic differences between serum and liver were related to a higher likelihood of development of mild recurrent disease after transplant (p=0.039).
    Virology 07/2010; 402(2):248-55. · 3.35 Impact Factor
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    ABSTRACT: The frequency that multiple different subtypes of hepatitis C virus (HCV) simultaneously infect a given individual is controversial. To address this question, heteroduplex mobility analysis (HMA) of portions of the HCV core and envelope 1 region was optimized for sensitive and specific detection of mixtures of HCV genomes of different genotype or subtype. Using the standard HCV genotyping approach of 5'-untranslated region (UTR) analysis, 28 of 374 (7.5%) chronic hepatitis C research subjects were classified as having either multiple-subtype HCV infections (n = 21) or switching HCV subtypes over time (n = 7), the latter pattern implying viral superinfection. Upon retesting of specimens by HMA, 25 of 28 multiple-subtype results could not be reproduced. All three patients with positive results were injection drug users with potential multiple HCV exposures. To address the hypothesis of tissue sequestration of multiple-subtype HCV infections, liver (n = 22), peripheral blood mononuclear cell (n = 13), perihepatic lymph node (n = 16), and serum (n = 19) specimens from 23 subjects with end-stage hepatitis C were collected and analyzed by the HMA technique. Whereas 5'-UTR results implicated mixed-subtype HCV infections in 2 subjects, HMA testing revealed no evidence of a second HCV subtype in any tissue compartment (0 of 70 compartments [0%]) or within any given subject (0 of 23 subjects [0%]). In summary, a large proportion of mixed-genotype and switching-genotype patterns generated by 5'-UTR analysis were not reproducible using the HMA approach, emphasizing the need for additional study.
    Journal of Virology 09/2008; 82(15):7524-32. · 5.08 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV) envelope glycoprotein co-evolution was studied in 14 genotype 1-infected and treatment-naive subjects, including 7 with mild and 7 with severe liver disease. Cassettes encoding the envelope 1 gene (E1) and hypervariable region (HVR1) of the envelope 2 gene were isolated at 38 different time points over 81 follow-up years. There were no significant differences in age, gender, alcohol use, or viral load between the mild and severe disease groups. Virus from subjects with severe disease had significantly slower evolution in HVR1, and significant divergent evolution of E1 quasispecies, characterized by a preponderance of synonymous mutations, compared to virus from subjects with mild disease. Phylogenetic comparisons indicated higher similarity between amino acid sequences of the E1 and HVR1 regions with mild disease versus severe disease (r=0.44 versus r=0.17, respectively; P=0.01). In summary, HCV envelope quasispecies co-evolution differs during mild versus severe disease.
    Virology 07/2008; 375(2):580-91. · 3.37 Impact Factor