Epochal Evolution of GGII.4 Norovirus Capsid Proteins from 1995 to 2006

Abstract

Noroviruses are the causative agents of the majority of viral gastroenteritis outbreaks in humans. During the past 15 years, noroviruses of genotype GGII.4 have caused four epidemic seasons of viral gastroenteritis, during which four novel variants (termed epidemic variants) emerged and displaced the resident viruses. In order to understand the mechanisms and biological advantages of these epidemic variants, we studied the genetic changes in the capsid proteins of GGII.4 strains over this period. A representative sample was drawn from 574 GGII.4 outbreak strains collected over 15 years of systematic surveillance in The Netherlands, and capsid genes were sequenced for a total of 26 strains. The three-dimensional structure was predicted by homology modeling, using the Norwalk virus (Hu/NoV/GGI.1/Norwalk/1968/US) capsid as a reference. The highly significant preferential accumulation and fixation of mutations (nucleotide and amino acid) in the protruding part of the capsid protein provided strong evidence for the occurrence of genetic drift and selection. Although subsequent new epidemic variants differed by up to 25 amino acid mutations, consistent changes were observed in only five positions. Phylogenetic analyses showed that each variant descended from its chronologic predecessor, with the exception of the 2006b variant, which is more closely related to the 2002 variant than to the 2004 variant. The consistent association between the observed genetic findings and changes in epidemiology leads to the conclusion that population immunity plays a role in the epochal evolution of GGII.4 norovirus strains.Since the beginning of viral gastroenteritis outbreak surveillance in the early 1990s, noroviruses have become recognized as the major cause of reported outbreaks of acute viral gastroenteritis worldwide. Noroviruses form a genus within the family Caliciviridae and are genetically and antigenically highly variable. Currently, five distinct genogroups (GGs) are recognized. Strains belonging to GGI, GGII, and GGIV are known to cause infections in humans. The GGs have been subdivided further into genotypes, defined by a minimum amino acid sequence identity over the complete capsid sequence of 80% (1).The strains most commonly identified as the cause of outbreaks belong to genotype GGII.4. In The Netherlands, this was the case for 68% of all norovirus outbreaks that were characterized during 12 years of surveillance and for up to 81% of all health care-related outbreaks. Since their first detection in The Netherlands in January 1995, the GGII.4 strains have consistently been present in the Dutch population (46). These observations are in agreement with those of other surveillance studies worldwide (3,4,15,17,29,36,55).During the past 15 years, four epidemic norovirus seasons have occurred, in the winters of 1995-1996, 2002-2003, 2004-2005, and 2006-2007. These worldwide epidemics were invariantly caused by the predominant genotype, GGII.4, and were attributed to the emergence of new variant lineages of this genotype (4,3...

Genetic diversity of noroviruses in Brazil

“…NoV GII.4 is the most prevalent genotype and has been associated with global epidemics since the mid1990s, mainly due to the emergence of new variants of GII.4 lineages that occurs in two-four-year intervals (Siebenga et al 2007, Zheng et al 2010.…”

Norovirus vaccines: Correlates of protection, challenges and limitations

“…GII.4 NoVs are continuously changing and viral variants emerge every couple of years. [32][33][34][35] The use of VLPs revealed the ability of the surface-exposed P2 subdomain (279-405) to interact with neutralizing antibodies and NoV-specific carbohydrate-binding ligands. The surface exposed, highly variable sites of the P2 subdomain (epitopes A to E) undergo changes that were associated with the emergence of new strains causing NoV outbreaks.…”

“…Data show that new NoV variants (specifically GII.4) appear every 2-7 y as a result of genetic drift, an observation compatible with the immune escape mechanism observed with influenza A virus. 32,38 The binding profile of GII.4 to HBGAs facilitates the infection of 80-95% of the population. This suggests that this interaction is subject to immune pressure and may partially explain the predominance of GII.4 NoV. 39,40 Bull et al 41 reviewed the role of receptor switching, sequence space, duration of herd immunity and replication fidelity on the evolution of NoV. As previously described the sequence similarity of the NoV capsid protein residues is not a straightforward predictor of HBGA binding.…”

“…Recent reports suggest that the major capsid proteins of GII.4 are rapidly evolving leading to new viral strains with altered antigenicity. 32,38,43,45 Antigenic variation of RNA viruses, including NoVs, is successfully associated with evasion of the host immunity. It is suggested that GI NoVs have a conserved network of amino-acids required for capsid integrity.…”

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“…In addition, norovirus is resistant to freezing, heating and can tolerate commonly used disinfectants, including alcohol and quaternary ammonium compounds better than other viruses 9,10 . The combination of these properties allows norovirus to survive in external environments for long periods.…”