**5. Replicative cycle of RSV**

#### **5.1 Entry**

RSV infection mostly occurs in the apical side of ciliated cells and type 1 pneumocyte; however, several reports suggested the presence of RSV RNA in the

### *Respiratory Syncytial Virus DOI: http://dx.doi.org/10.5772/intechopen.104771*

extrapulmonary sites and fluids, but more investigations are required [104–107]. RSV entry has two major phases; the first step is virion attachment to the host cell and the next step is the fusion of viral and host cell membranes in which host factors can involve in both or any individual phases [52]. Heparin-binding domain located between mucin-rich domains of G protein interacts with the unbranched disaccharide polymers specifically glycosaminoglycans (GAGs) connected to transmembrane proteins on the cell surface for the attachment observed in multiple cell culture studies [108–110]. Variation of G protein lacking heparin-binding domain showed viral attachment indicating the involvement of other regions of G protein during attachment [108]. Negatively charged regions of heparin sulfate contribute mostly and iduronic acid-containing GAG contributes minimally to the attachment [111–113]. Heparan sulfate proteoglycans (HSGP) act as the receptor for G protein in cell lines; however, recombinant RSV without G protein showed its infectivity; in contrast, HSGP does not express in ciliated epithelial cells, but G protein is still essential for infection in vivo [114–116]. However, the apical side of ciliated cells, which is the major site of RSV infection lack heparin sulfate indicating the involvement of other host factors, specifically, fractalkine receptor CX3C-chemokine receptor 1 (CX3CR1) bind to CX3C motif of G protein for the attachment [117, 118]. CX3CR1 expressed on the ciliated cells, acts as the receptor of G protein by interacting with its CX3C motif and mutations in the CX3C motif of G protein reduces RSV infection in vivo [117, 119–121]. F protein is involved in the viral attachment because RSV lacking G and SH proteins grows in cell culture studies and it interacts with heparin sulfate like G protein causing attachment and subsequent infection [63, 122, 123]. Almost 50% infection was observed after heparinase treatment and without GAG synthesis while RSV has F protein suggesting the interaction of F with other host factors; particularly, F protein facilitates entry by interacting with intercellular adhesion molecule 1, insulin-like growth factor 1, epidermal growth factor receptor, and nucleolin [124–127]. Host and viral membrane then fuse after attachment so that viral particles can enter the cytoplasm and this fusion process is pH-independent and insensitive to lysosomal acidification [128, 129]. RSV infection induces an actin mediated rearrangement followed by plasma membrane blebbing and excess fluid uptake causing internalization of viral particles in a Rab5 positive macropinisome and this endocytic entry depends on the activation of F protein by a second proteolytic cleavage catalyzed by furin-like enzymes after endocytosis observed in A549 cell [130].
