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Journal of Virology, January 2009, p. 1071-1082, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01501-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Genetic History of Hepatitis C Virus in East Asia {triangledown}

Oliver G. Pybus,1*,{dagger} Eleanor Barnes,2,{dagger} Rachel Taggart,2 Philippe Lemey,1 Peter V. Markov,1 Bouachan Rasachak,3 Bounkong Syhavong,3 Rattanaphone Phetsouvanah,3,5 Isabelle Sheridan,2 Isla S. Humphreys,2 Ling Lu,4 Paul N. Newton,3,5 and Paul Klenerman2

Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom,1 The Peter Medawar Building for Pathogen Research, University of Oxford, South Parks Road, Oxford OX1 3SY, United Kingdom,2 Wellcome Trust-Mahosot Hospital-Oxford University Tropical Medicine Research Collaboration, Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos,3 Division of Gastroenterology-Hepatology and Nutrition, University of Utah, Salt Lake City, Utah,4 Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Churchill Hospital, University of Oxford, Oxford OX3 7LJ, United Kingdom5

Received 17 July 2008/ Accepted 20 October 2008

The hepatitis C virus (HCV), which currently infects an estimated 3% of people worldwide, has been present in some human populations for several centuries, notably HCV genotypes 1 and 2 in West Africa and genotype 6 in Southeast Asia. Here we use newly developed methods of sequence analysis to conduct the first comprehensive investigation of the epidemic and evolutionary history of HCV in Asia. Our analysis includes new HCV core (n = 16) and NS5B (n = 14) gene sequences, obtained from serum samples of jaundiced patients from Laos. These exceptionally diverse isolates were analyzed in conjunction with all available reference strains using phylogenetic and Bayesian coalescent methods. We performed statistical tests of phylogeographic structure and applied a recently developed "relaxed molecular clock" approach to HCV for the first time, which indicated an unexpectedly high degree of rate variation. Our results reveal a >1,000-year-long development of genotype 6 in Asia, characterized by substantial phylogeographic structure and two distinct phases of epidemic history, before and during the 20th century. We conclude that HCV lineages representing preexisting and spatially restricted strains were involved in multiple, independent local epidemics during the 20th century. Our analysis explains the generation and maintenance of HCV diversity in Asia and could provide a template for further investigations of HCV spread in other regions.

* Corresponding author. Mailing address: Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, United Kingdom. Phone: 44 1865 271274. Fax: 44 1865 271249. E-mail: oliver.pybus{at}zoo.ox.ac.uk

{triangledown} Published ahead of print on 29 October 2008.

{dagger} O.G.P. and E.B. contributed equally.

Journal of Virology, January 2009, p. 1071-1082, Vol. 83, No. 2
0022-538X/09/$08.00+0     doi:10.1128/JVI.01501-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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