This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wang, X.-H.
Right arrow Articles by Ray, S. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wang, X.-H.
Right arrow Articles by Ray, S. C.

 Previous Article  |  Next Article 

Journal of Virology, June 2007, p. 6513-6522, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02276-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Progression of Fibrosis during Chronic Hepatitis C Is Associated with Rapid Virus Evolution{triangledown}

Xiao-Hong Wang,1,5 Dale M. Netski,1 Jacquie Astemborski,4 Shruti H. Mehta,4 Michael S. Torbenson,2 David L. Thomas,1,4 and Stuart C. Ray1,3*

Departments of Medicine,1 Pathology,2 Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland,3 Department of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland,4 Southwest Hospital, Third Military Medical University, Chongqing, Peoples Republic of China 4000385

Received 17 October 2006/ Accepted 20 February 2007

Hepatic fibrosis is the primary mediator of disease due to chronic infection with hepatitis C virus (HCV). HCV exists as a quasispecies in each infected individual, and longitudinal viral sequence changes may reveal viral dynamics and the selection pressures applied by the host immune system. Thus, we hypothesized that patterns of sequence change might reveal the immunopathogenesis of fibrosis progression. We tested this hypothesis by studying individuals enrolled in a prospective study of chronic HCV-related hepatic fibrosis with little or no fibrosis at first biopsy (stage 0 or 1) and a second planned liver biopsy sample obtained 4 years later. Serum was obtained from five individuals with fast progression (FP; defined as a >2-stage change between visits) and 10 carefully matched individuals with slow progression (SP; defined as a <2-stage change between visits). We sequenced multiple cloned hemigenomic cDNAs from each person spanning six genes (core through NS3). Phylogenetic analysis revealed temporal shifts in phylogenetic clustering over time, suggesting frequent quasispecies replacement rather than simple diversification. In addition, mixed infections were detected in three subjects, with coexistence in two subjects (one FP, one SP) of subtypes 1a and 1b throughout the 4-year biopsy interval. Subjects with FP had a higher rate of evolution than subjects with SP, with a preponderance of synonymous changes, suggesting purifying selection, except in hypervariable region 1, where positive selection pressure is frequently detected. Thus, in a small but carefully matched cohort we found evidence for rapid neutral evolution of HCV in persons with rapid progression of hepatic fibrosis, suggesting higher turnover of infected cells.

* Corresponding author. Mailing address: Viral Hepatitis Center, Div. of Inf. Dis., Department of Medicine, Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Suite 114, Baltimore, MD 21231. Phone: (410) 955-0349. Fax: (410) 614-7564. E-mail: sray{at}jhmi.edu

{triangledown} Published ahead of print on 28 February 2007.

Journal of Virology, June 2007, p. 6513-6522, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.02276-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»