Table S1 Enhanced gene expression in brains incl. OBs of intranasally VSV-infected Ifit2 2/2 versus wt mice at 6 d.p.i. Wt or Ifit2 2/2 mice were intranasally VSV-infected with 4610 2 pfu, and at 2 or 6 d.p.i., brain (incl. OB) RNA expression profiles were obtained by microarray. Genes are ranked by their ''fold expression level in Ifit2 2/2 over wt at 6 d.p.i.''. Only genes with at least 3-fold higher expression level in Ifit2 2/2 are included. Note: The Ifit1/ISG56 probe of the Illumina mouse Ref-8 chip is defective and therefore the gene is not included in this list. (PDF) Immunogenetic Mechanisms Driving Norovirus GII.4 Antigenic Variation Noroviruses are the principal cause of epidemic gastroenteritis worldwide with GII.4 strains accounting for 80% of infections. The major capsid protein of GII.4 strains is evolving rapidly, resulting in new epidemic strains with altered antigenic potentials. To test if antigenic drift may contribute to GII.4 persistence, human memory B cells were immortalized and the resulting human monoclonal antibodies (mAbs) characterized for reactivity to a panel of time-ordered GII.4 virus-like particles (VLPs). Reflecting the complex exposure history of the volunteer, human anti-GII.4 mAbs grouped into three VLP reactivity patterns; ancestral (1987–1997), contemporary (2004–2009), and broad (1987–2009). NVB 114 reacted exclusively to the earliest GII.4 VLPs by EIA and blockade. NVB 97 specifically bound and blocked only contemporary GII.4 VLPs, while NBV 111 and 43.9 exclusively reacted with and blocked variants of the GII.4.2006 Minerva strain. Three mAbs had broad GII.4 reactivity. Two, NVB 37.10 and 61.3, also detected other genogroup II VLPs by EIA but did not block any VLP interactions with carbohydrate ligands. NVB 71.4 cross-neutralized the panel of time-ordered GII.4 VLPs, as measured by VLP-carbohydrate blockade assays. Using mutant VLPs designed to alter predicted antigenic epitopes, two evolving, GII.4-specific, blockade epitopes were mapped. Amino acids 294–298 and 368–372 were required for binding NVB 114, 111 and 43.9 mAbs. Amino acids 393–395 were essential for binding NVB 97, supporting earlier correlations between antibody blockade escape and carbohydrate binding variation. These data inform VLP vaccine design, provide a strategy for expanding the cross-blockade potential of chimeric VLP vaccines, and identify an antibody with broadly neutralizing therapeutic potential for the treatment of human disease. Moreover, these data support the hypothesis that GII.4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution. Noroviruses (NoVs) are the leading cause of severe viral gastroenteritis and are responsible for 50% of all acute gastroenteritis outbreaks in the United States and Europe [1] . Although the severity of disease is usually moderate, lasting 1-3 days, infection can be especially virulent in young children, the elderly, and the immunocompromised, with the latter group experiencing chronic diarrhea and virus shedding for over a year [2] [3] [4] [5] [6] [7] [8] . Importantly, it is estimated that 200,000 people die each year from norovirus infections, primarily children in the developing world [9] . An effective vaccine would be particularly advantageous for the very young and aged populations, military personnel, children and healthcare providers, food handlers, cruise ship passengers, and populations of the developing world [10] . Immunotherapeutics are especially needed for treating immunosuppressed populations experiencing long-term infections with chronic diarrhea. The lack of understanding of the extensive antigenic relationships among the large number of norovirus strains and the complex relationship between host protective immunity and virus antigenic heterogeneity are the primary obstacles to norovirus vaccine development.