Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing

PLoS Pathogens

Erica H. Parrish¹  Beatrice H. Hahn²  Barton F. Haynes²  Shuyi Wang³  Mark B. Stoddard³  Gerald H. Learn³  Peter Hraber³  Ruy M. Ribeiro³  Hui Li³  Tanmoy Bhattacharya⁴  Lily M. Blair⁴  Alan S. Perelson⁵  George M. Shaw⁵  Elena E. Giorgi⁵  Paul A. Goepfert⁵  Bette T. Korber⁵  Michael S. Saag⁶  Thomas N. Denny⁶ 

[1] Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America;Duke University School of Medicine, Durham, North Carolina, United States of America;Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Santa Fe Institute, Santa Fe, New Mexico, United States of America;Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America;University of Alabama at Birmingham, Birmingham, Alabama, United States of America

关键词: Sequence analysis;    Viral genomics;    DNA sequence analysis;    HIV-1;    Hepatitis C virus;    Phylogenetic analysis;    Species diversity;    Viral transmission;    infection;   

DOI  :  10.1371/journal.ppat.1002880

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.

【 授权许可】

CC BY