Evidence for separation of HCV subtype 1a into two distinct clades

Journal of Viral Hepatitis

Early View (Articles online in advance of print)
Published Online: 21 Jun 2010
© 2010 Blackwell Publishing Ltd

B. E. Pickett 1 , R. Striker 2,3 and E. J. Lefkowitz 1
1 Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA ; 2 W. S. Middleton Memorial Veterans Administration Hospital, Madison, WI, USA; and 3 Departments of Medicine and Medical Microbiology & Immunology, University of Wisconsin, Madison, WI, USA

Correspondence to Elliot Lefkowitz, BBRB 276/11, 1530 3rd Ave S, Birmingham, AL 35294-2170, USA. E-mail: elliotl@uab.edu

KEYWORDS
bioinformatics • drug resistance • hepatitis C virus • phylogeny • selection pressure

ABSTRACT
Summary. The nucleotide sequence diversity present among hepatitis C virus (HCV) isolates allows rapid adjustment to exterior forces including host immunity and drug therapy. This viral response reflects a combination of a high rate of replication together with an error-prone RNA-dependent RNA polymerase, providing for the selection and proliferation of the viruses with the highest fitness. We examined HCV subtype 1a whole-genome sequences to identify positions contributing to genotypic and phenotypic diversity. Phylogenetic tree reconstructions showed two distinct clades existing within the 1a subtype with each clade having a star-like tree topology and lacking definite correlation between time or place of isolation and phylogeny. Identification of significant phylogenetically informative sites at the nucleotide level revealed positions not only contributing to clade differentiation, but which are located at or proximal to codons associated with resistance to protease inhibitors (NS3 Q41) or polymerase inhibitors (NS5B S368). Synonymous/nonsynonymous substitution mutation analyses revealed that the majority of nucleotide mutations yielded synonymous amino acids, indicating the presence of purifying selection pressure across the polyprotein with pockets of positive selection also being detected. Despite evidence for divergence at several loci, certain 1a characteristics were preserved including the length of the alternative reading frame/F protein (ARF/F) gene, and a subtype 1a-specific phosphorylation site in NS5A (S349). Our analysis suggests that there may be strain-specific differences in the development of antiviral resistance to viruses infecting patients who are dependent on the genetic variation separating these two clades.

Received January 2010; accepted for publication April 2010

DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1365-2893.2010.01342.x About DOI
 
Source