Positive Selection Results in Frequent Reversible Amino Acid Replacements in the G Protein Gene of Human Respiratory Syncytial Virus

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Abstract
Human respiratory syncytial virus (HRSV) is the major cause of lower respiratory tract infections in children under 5 years of age and the elderly, causing annual disease outbreaks during the fall and winter. Multiple lineages of the HRSVA and HRSVB serotypes co-circulate within a single outbreak and display a strongly temporal pattern of genetic variation, with a replacement of dominant genotypes occurring during consecutive years. In the present study we utilized phylogenetic methods to detect and map sites subject to adaptive evolution in the G protein of HRSVA and HRSVB. A total of 29 and 23 amino acid sites were found to be putatively positively selected in HRSVA and HRSVB, respectively. Several of these sites defined genotypes and lineages within genotypes in both groups, and correlated well with epitopes previously described in group A. Remarkably, 18 of these positively selected tended to revert in time to a previous codon state, producing a “flip-flop” phylogenetic pattern. Such frequent evolutionary reversals in HRSV are indicative of a combination of frequent positive selection, reflecting the changing immune status of the human population, and a limited repertoire of functionally viable amino acids at specific amino acid sites. As part of the Viral Genetic Diversity Network (VGDN), we sequenced the second variable region (G2) of the G protein of human respiratory syncytial virus (HRSV) A and B from 568 patients sampled during 11 consecutive HRSV seasons (1995–2005) in the state of São Paulo, Brazil. A total of 933 HRSVA and 673 HRSB time-stamped sequences, including those sampled here and globally, was used for phylogenetic inference and the analysis of selection pressures. We identified 18 positively selected sites in both HRSVA (9 sites) and HRSVB (9 sites) that tended to revert in time to their previous codon state (i.e. exhibited a “flip-flop” pattern). We argue that these common evolutionary reversals are indicative of frequent positive selection, reflecting the changing immune status of the human population, coupled with a limited repertoire of functional viable amino acids at specific sites. This information is of particular importance since the ectodomain of the G protein is also a target site in vaccines that have so far proven unsuccessful and because it constitutes a significant step towards describing and understanding the immune-escape repertoire of this major human pathogen.

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