Variations in the Hemagglutinin of the 2009 H1N1 Pandemic Virus: Potential for Strains with Altered Virulence Phenotype?

PLoS Pathogens

Adolfo Garcia-Sastre¹  Hongxia Shao¹  Haichen Song¹  Rafael A. Medina¹  Lindomar Pena¹  Erin M. Sorrell¹  Kemin Xu²  Matthew Angel²  Jianqiang Ye²  Yibin Cai²  Danielle Hickman²  Balaji Manicassamy²  Daniel R. Perez² 

[1] Department of Veterinary Medicine, University of Maryland, College Park, Maryland, United States of America;Virginia-Maryland Regional College of Veterinary Medicine, College Park, Maryland, United States of America

关键词: H1N1;    Ferrets;    Mouse models;    Microbial mutation;    Respiratory infections;    Influenza viruses;    Influenza;    Antigens;   

DOI  :  10.1371/journal.ppat.1001145

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

A novel, swine-origin influenza H1N1 virus (H1N1pdm) caused the first pandemic of the 21st century. This pandemic, although efficient in transmission, is mild in virulence. This atypical mild pandemic season has raised concerns regarding the potential of this virus to acquire additional virulence markers either through further adaptation or possibly by immune pressure in the human host. Using the mouse model we generated, within a single round of infection with A/California/04/09/H1N1 (Ca/04), a virus lethal in mice—herein referred to as mouse-adapted Ca/04 (ma-Ca/04). Five amino acid substitutions were found in the genome of ma-Ca/04: 3 in HA (D131E, S186P and A198E), 1 in PA (E298K) and 1 in NP (D101G). Reverse genetics analyses of these mutations indicate that all five mutations from ma-Ca/04 contributed to the lethal phenotype; however, the D131E and S186P mutations—which are also found in the 1918 and seasonal H1N1 viruses—in HA alone were sufficient to confer virulence of Ca/04 in mice. HI assays against H1N1pdm demonstrate that the D131E and S186P mutations caused minor antigenic changes and, likely, affected receptor binding. The rapid selection of ma-Ca/04 in mice suggests that a virus containing this constellation of amino acids might have already been present in Ca/04, likely as minor quasispecies.

【 授权许可】

CC BY