Phylogenetic Relationships and Molecular Adaptation Dynamics of Human Rhinoviruses

Human rhinoviruses (HRVs) are responsible for nearly 50% of all common cold infections. Ordinarily, HRV infections are mild and self-limiting; nonetheless, every year they result in significant loss of economic productivity and substantial inappropriate antibiotic use. Development of effective vaccine and antiviral prophylaxis against HRV has been hampered by the extensive antigenic diversity present among the nearly 100 serotypes. To gain new insights into the evolutionary processes that create the genetic diversity present among HRVs, we tested for recombination and selection for individual genes and the coding genome for 45 HRV serotypes using estimated phylogenetic relationships. Although the structural capsid genes and nonstructural genes recovered incongruent tree topologies, no recombination was detected using substitution methods. Therefore, the coding genome was determined to be appropriate for phylogenetic tests. Results of the Shimodaira-Hasegawa (SH) test support the hypothesis that the capsid genes recover a different evolutionary history than the nonstructural genes. Our best phylogenetic estimate based on the coding genome suggests that HRV-B is more closely related to enterovirus than to HRV-A; however, several alternative phylogenetic hypotheses were not rejected by the SH test. Positive selection was examined by using two different approaches; d(N)/d(S) rate ratio and the physicochemical phenotypes for 31 amino acid properties. Analyses using d(N)/d(S) failed to detect positive selection. However, protein phenotypic expression appears to be a more sensitive approach. There was extensive stabilizing and destabilizing positive selection in HRV-A major and HRV-B serotypes for all proteins, except in 3A in HRV-B, which overlapped with functional, structural, and to a greater extent in uncharacterized genomic regions. In contrast, the evolution of HRV-A minor serotypes appears to be driven primarily by destabilizing selection. Our results demonstrate that HRV-A major, HRV-A minor, and HRV-B serotypes have not been similarly influenced by purifying selection.