Hepatitis C virus (HCV) infection is one of the major concerns in public health. Currently, optimal antiviral therapy with pegylated interferon-alpha plus ribavirin, cures ~50% of patients infected with HCV genotype 1 and ~80% of patients infected with HCV genotypes 2 and 3. One of the difficulties regarding our understanding on treatment resistance is related to the nature of current antiviral agents. Both interferon and ribavirin have long been known for their broad-spectrum antiviral activity by creating a non-specific antiviral status rather than the direct interaction with viruses. Consequently, no explicit targets on HCV genome have been documented. Studies on drug resistance with these agents have generated very controversial data through conventional approaches that frequently focus on short domains of the HCV rather than the entire viral genome. Using a novel long RT-PCR and cloning technology and well characterized serum samples from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial (HALT-C), we propose a viral sequencing project through which viral mechanisms for the resistance to antiviral therapy will be exhaustively examined at multiple levels. ? HYPOTHESIS: HCV resistance to antiviral therapy is associated with region-dependent mutations of viral quasispecies at either single variants or the population level. ? Aim 1: To explore genetic signatures at both HCV isolate and quasispecies levels in null responders infected with HCV genotype 1a. The full-length HCV quasispecies profiles at the baseline will be generated from patients with either null or sustained virological responses (SVR), followed by comparative analyses to identify potential genetic signatures that are associated with the treatment resistance. ? Aim 2: To demonstrate if there are distinct quasispecies structures of HCV genotype 2 in terms of the high response rate to the antiviral therapy. The full-length HCV quasispecies profiles will be generated from twenty SVRs with HCV genotype 2a, followed by comparative analyses with those derived from HCV genotype 1a. ? Aim 3: To characterize mutational patterns associated with HCV re-emergence in patients with relapse after initial response to antiviral therapy. The relapse indicates the survival of HCV from a putative population bottleneck formed under antiviral therapy. How does HCV respond to such """"""""in vivo"""""""" population bottlenecks? ? This issue will be addressed through a sequential comparative analysis of full-length HCV quasispecies profiles. Data from these studies will have immediate applications for rational design of future HCV antiviral therapy in which PegIFN-( and ribavirin are still the core components. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK080711-01
Application #
7439547
Study Section
Special Emphasis Panel (ZDK1-GRB-9 (J1))
Program Officer
Doo, Edward
Project Start
2008-03-01
Project End
2013-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
1
Fiscal Year
2008
Total Cost
$294,000
Indirect Cost
Name
Saint Louis University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Wang, Weihua; Ren, Yi; Lu, Yang et al. (2017) Template-dependent multiple displacement amplification for profiling human circulating RNA. Biotechniques 63:21-27
Ren, Yi; Wang, Weihua; Zhang, Xiaoan et al. (2016) Evidence for deleterious hepatitis C virus quasispecies mutation loads that differentiate the response patterns in IFN-based antiviral therapy. J Gen Virol 97:334-43
Lin, Jianguo; Wang, Weihua; Xu, Yanjuan et al. (2015) Patterns of longitudinal change in hepatitis C virus neutralization titers correlate with the outcome of peginterferon and ribavirin combination therapy. J Med Virol 87:821-8
Wang, Weihua; Zhang, Xiaoan; Xu, Yanjuan et al. (2014) High-resolution quantification of hepatitis C virus genome-wide mutation load and its correlation with the outcome of peginterferon-alpha2a and ribavirin combination therapy. PLoS One 9:e100131
Wang, Weihua; Zhang, Xiaoan; Xu, Yanjuan et al. (2013) Viral categorization and discovery in human circulation by transcriptome sequencing. Biochem Biophys Res Commun 436:525-9
Lu, Yang; Xu, Yanjuan; Di Bisceglie, Adrian M et al. (2013) Comprehensive cloning of patient-derived 9022-bp amplicons of hepatitis C virus. J Virol Methods 191:105-12
Zhang, Xiaoan; Ryu, Soo Hyung; Xu, Yanjuan et al. (2011) The Core/E1 domain of hepatitis C virus genotype 4a in Egypt does not contain viral mutations or strains specific for hepatocellular carcinoma. J Clin Virol 52:333-8
Wang, Weihua; Lin, Jianguo; Tan, De et al. (2011) Divergent quasispecies evolution in de novo hepatitis C virus infection associated with bone marrow transplantation. Biochem Biophys Res Commun 414:148-52
Pickett, B E; Striker, R; Lefkowitz, E J (2011) Evidence for separation of HCV subtype 1a into two distinct clades. J Viral Hepat 18:608-18
Zhang, Xiaoan; Fan, Xiaofeng; Xu, Yanjuan et al. (2010) Enhanced protocol for determining the 3' terminus of hepatitis C virus. J Virol Methods 167:158-64

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