Epidemiology, classification and evolution of human rhinoviruses

Abstract

Human rhinoviruses (HRV) are extremely common human respiratory pathogens, most commonly associated with mild upper respiratory tract infections. The three known species of HRV (HRV-A, -B and –C) are members of the family Picornaviridae and genus Enterovirus. In contrast to the enterovirus (EV-A-D) species that commonly infect the gut, HRV are generally thought to be acid labile with replication restricted to the respiratory tract. Investigations of the clinical correlations of HRV infections detected on diagnostic screening of respiratory specimens demonstrated no specific association between HRV variant and clinical presentation. For example, similar species distributions were observed in patients admitted to the ITU and those discharged with minor illness. Unexpectedly, screening of stool specimens for HRV showed a prevalence of 10% with viral loads similar to EV infections. These findings suggested that a reappraisal of HRV tropism and disease associations may be warranted. HRV-A and -B isolates were originally classified into 100 serotypes by serological neutralisation properties. As HRV-C is difficult to isolate, no attempt had been previously made to classify the wealth of available HRV-C sequences. To facilitate definition of novel HRV types and classification of HRV-C, a system was devised to divide HRV sequences into genotypically defined types. Pairwise VP1 nucleotide p-distance analysis revealed distinct thresholds between inter- and intra- type divergence and available sequences were classified into 77 HRV-A, 29 -B and 51 -C types. This provides a standardised basis for type definition and identification, allowing consistency in studies of genetic diversity, epidemiology and evolution. It has been adopted by the ICTV Picornavirus Study Group for classification of HRV. Although the occurrence of recombination has been documented within the coding region of EV, analysis of dated HRV sequences revealed an overall lack of intra-species recombination between three coding regions of HRV-B and -C. In contrast, full HRV-A type groups appeared to have been subject to a large number of recombination events, suggesting extensive recombination during the period of its diversification into types. Putative recombination breakpoints localised to the non-structural region. Within HRV-A and HRV-B, recombination within the 5ˈUTR was infrequent. However, over 60% of analysed HRV-C strains grouped within the HRV-A clade and two recombination hotspots were identified. An additional interspecies recombination event was detected between HRV-A/C in the 2A coding region, with putative breakpoints mapping to the boundaries of the C-terminal domain of the proteinase. The studies within this thesis provide evidence for a broadened understanding of the clinical significance of HRV. In addition, the assignment of HRV sequences into genotypically defined types allowed description of the observed genetic diversity and completion of analysis which reaffirmed the sporadic nature of recombination within the coding region of HRV.