Influence of respiratory syncytial virus strain differences on pathogenesis and immunity

Abstract

Molecular epidemiology studies have provided convincing evidence of antigenic and sequence variability among respiratory syncytial virus (RSV) isolates. Circulating viruses have been classified into two antigenic groups (A and B) that correlate with well-delineated genetic groups. Most sequence and antigenic differences (both inter- and intra-groups) accumulate in two hypervariable segments of the G-protein gene. Sequences of the G gene have been used for phylogenetic analyses. These studies have shown a worldwide distribution of RSV strains with both local and global replacement of dominant viruses with time. Although data are still limited, there is evidence that strain variation may contribute to differences in pathogenicity. In addition, there is some but limited evidence that RSV variation may be, at least partially, immune (antibody) driven. However, there is the paradox in RSV that, in contrast to other viruses (e.g., influenza viruses) the epitopes recognized by the most effective RSV-neutralizing antibodies are highly conserved. In contrast, antibodies that recognize strain-specific epitopes are poorly neutralizing. It is likely that this apparent contradiction is due to the lack of a comprehensive knowledge of the duration and specificities of the human antibody response against RSV antigens. Since there are some data supporting a group- (or clade-) specific antibody response after a primary infection in humans, it may be wise to consider the incorporation of strains representative of groups A and B (or their antigens) in future RSV vaccine development.

Figure 1

Figure 2. Scheme of the F protein primary structure

The sequence length is indicated above the main rectangle. Black boxes denote the hydrophobic signal peptide (SP), fusion peptide (FP) and transmembrane region (TM). Shaded boxes symbolize heptad repeat sequences, HRA and HRB and the two arrows indicate the location of the proteolytic cleavage sites. Vertical lines denote the location of the indicated amino acid changes selected in escape mutants described in the following articles: (Arbiza et al. 1992;Lopez et al. 1998;Crowe et al. 1998;Zhao et al. 2004a;Zhao et al. 2004b). These amino acid changes have been grouped in antigenic sites I, II and IV as shown above the main rectangle.

Figure 3. Scheme of the G protein primary structure

The sequence length is indicated above the main rectangle. Two mucin-like variable regions of the G protein ectodomain are indicated. Black dots denote Cys residues, black arrowheads denote N-glycosylation sites and short vertical lines (below the main rectangle) O-glycosylation sites. The black box delineates the transmembrane region. The grey boxes delineate the location of conserved and group-specific epitopes in the central segment and the strain-specific epitopes in the C-terminal mucin-like region, respectively (Garcia-Barreno et al. 1990;Rueda et al. 1991;Rueda et al. 1994;Rueda et al. 1995;Martinez et al. 1997;Walsh et al. 1998). The continuous horizontal line denotes the segment of identical sequence (amino acids 164–176) in all RSV isolates and the broken horizontal line the segment of identical sequence (amino acids 163–189) in all RSV group A isolates.