Phylodynamics and dispersal of HRSV entails its permanence in the general population in between yearly outbreaks in children

Abstract

Background: Human respiratory syncytial virus (HRSV) is one of the major etiologic agents of respiratory tract infections among children worldwide.

Methodology/principal findings: Here through a comprehensive analysis of the two major HRSV groups A and B (n=1983) which comprise of several genotypes, we present a complex pattern of population dynamics of HRSV over a time period of 50 years (1956-2006). Circulation pattern of HRSV revealed a series of expansions and fluctuations of co-circulating lineages with a predominance of HRSVA. Positively selected amino acid substitutions of the G glycoprotein occurred upon population growth of GB3 with a 60-nucleotide insertion (GB3 Insert), while other genotypes acquired substitutions upon both population growth and decrease, thus possibly reflecting a role for immune selected epitopes in linkage to the traced substitution sites that may have important relevance for vaccine design. Analysis evidenced the co-circulation and predominance of distinct HRSV genotypes in Brazil and suggested a year-round presence of the virus. In Brazil, GA2 and GA5 were the main culprits of HRSV outbreaks until recently, when the GB3 Insert became highly prevalent. Using Bayesian methods, we determined the dispersal patterns of genotypes through several inferred migratory routes.

Conclusions/significance: Genotypes spread across continents and between neighboring areas. Crucially, genotypes also remained at any given region for extended periods, independent of seasonal outbreaks possibly maintained by re-infecting the general population.

Figure 1. Global demographic history of HRSV genotypes.

Bayesian skyline plots of complete HRSV sequences of HRSVA (n = 1203) and HRSVB (n = 780). The y-axis represents a measure of relative genetic diversity presented as Ne.g reflecting the change in effective population (a surrogate for number of infections) over time for the complete set of HRSV sequences for HRSVA (n = 1204) and HRSVB (n = 778). The dotted lines define the likelihood bounds corresponding to a 95% confidence interval (CI). (…) - Upper and lower limits for HRSVA; (—) - Upper and lower limits for HRSVB. The arrow represents a shift in dynamics between HRSVA and HRSVB.

Figure 2. Population dynamics and genetic diversity of HRSV.

A) Bayesian skyline plots of HRSVA genotypes B) Bayesian skyline plots of HRSVB genotypes. Positively selected amino acid substitution sites are represented as previously described by Botosso et al. . The y-axis represents a measure of relative genetic diversity presented as Ne.g reflecting the change in effective number of infections over time.

Figure 3. Epidemiology and population dynamics of HRSV in São Paulo.

Bayesian skyline plots of HRSV genotypes prevalent in São Paulo (top) and seasonal distribution of HRSV cases in São Paulo during the 1995–2005 seasons are shown in the x-axis. GA1, GA3 GA7 and GB4 were excluded from the BSL analysis because of small sample size (n<10). The y-axis (on the left) represents a measure of relative genetic diversity presented as Ne.g reflecting the change in effective number of infections over time; where g is the average generation time. The y-axis (on the right) represents the number of samples in the study. (-) - Number of total samples collected during the period. (-) - Number of all HRSV positive cases identified with monoclonal antibodies and molecular characterization.

Figure 4. Plausible migration routes of HRSV.

A) Major HRSVA genotypes B) Main HRSVB genotypes c) Minor and sporadic HRSV genotypes. Migration routes and directionality were discerned from MCC phylogenetic trees and Bayes factor rates.