Recombination within the Pandemic Norovirus GII.4 Lineage

Abstract

e Norovirus (NoV) is the leading cause of viral gastroenteritis globally. Since 1996, NoV variants of a single genetic lineage, GII.4, have been associated with at least six pandemics of acute gastroenteritis and caused between 62 and 80% of all NoV outbreaks. The emergence of these novel GII.4 variants has been attributed to rapid evolution and antigenic variation in response to herd immunity; however, the contribution of recombination as a mechanism facilitating emergence is increasingly evident. In this study, we sought to examine the role that intragenotype recombination has played in the emergence of GII.4 variants. Using a genome-wide approach including 25 complete genome sequences generated as part of this study, 11 breakpoints were identified within the NoV GII.4 lineage. The breakpoints were located at three recombination hot spots: near the open reading frame 1/2 (ORF1/2) and ORF2/3 overlaps, as well as within ORF2, which encodes the viral capsid, at the junction of the shell and protruding domains. Importantly, we show that recombination contributed to the emergence of the recent pandemic GII.4 variant, New Orleans 2009, and a newly identified GII.4 variant, termed Sydney 2012. Reconstructing the evolutionary history of the GII.4 lineage reveals the widespread impact of both inter-and intragenotype recombination on the emergence of many GII.4 variants. Lastly, this study highlights the many challenges in the identification of true recombination events and proposes that guidelines be applied for identifying NoV recombinants.

Identification of a novel cellular target and a co-factor for norovirus infection – B cells & commensal bacteria

“…28 The most recent GII.4 pandemic strain is the GII.4-Sydney strain which emerged in 2012. 29 When a GII.4-Sydney HuNoVpositive stool sample was applied to the human B cell line BJAB, we detected significant albeit modest increases in viral genome copy number. As expected, viral genome replication was completely ablated by UV treatment and a polyclonal a-VP1 antibody fully neutralized infectivity.…”

Detection of Enteric Viruses in Fecal Specimens from Nonbacterial Foodborne Gastroenteritis Outbreaks in Tokyo, Japan between 1966 and 1983

“…The P2 domain is located on the outermost exterior surface of the capsid (14), and contains epitopes for neutralizing antibodies (15). Since the mid-1990s, NoV GII.4 has been the major cause of NoV-related gastroenteritis outbreaks (16). However, a new variant of NoV GII.17 was frequently detected in the 2014/2015 winter season (17).…”

Norovirus vaccines: Correlates of protection, challenges and limitations

“…11 Residues of the P2 subdomain of GII.4 are described to be under selective pressure and consequently leading to antigenic drift resulting in escape of the immune responses. 28,29,38,40 In summary, antigenic drift, strain recombination, 35 antigenic shift and the polymerase fidelity of NoVs 43 clearly contribute to the continuous propagation of GII.4. The evolution of GII.4, described as being epochal (long periods of status quo followed by outbursts of variation) over time generates escape mutants that are periodically selected for by herd immunity.…”

“…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.…”