Alternative conformations of a major antigenic site on RSV F

Jones, Harrison G.; Battles, Michael B.; Lin, Chun-Chi; Bianchi, Siro; Corti, Davide; McLellan, Jason S.

RSV F initially folds into a metastable prefusion conformation, with fusion peptides buried within the central cavity of the trimer [8] . During viral entry, RSV F triggers to undergo a dramatic conformational rearrangement from the prefusion to postfusion state. The triggering process results in release of the fusion peptides from the central cavity of the trimer and their insertion into the target-cell membrane, resulting in the formation of an unstable prehairpin intermediate. Collapse of this intermediate into the stable postfusion conformation brings the virus and host-cell membranes together, facilitating formation of a fusion pore and release of the viral genome into the target cell [7, 15] . However, the mechanism and underlying cause of RSV F triggering is not well understood. Recombinant virus expressing only the RSV F protein on its surface is sufficient for infection of immortalized cell lines in vitro, suggesting that RSV F can facilitate attachment and mediate fusion in the absence of the attachment glycoprotein [7, [20] [21] [22] . Potential RSV F receptors include nucleolin, EGFR, and heparan sulfate proteoglycans, among others [7, [23] [24] [25] [26] [27] , but the specific role each may play in the setting of natural infection remains to be defined. In addition, in vitro experiments have demonstrated that RSV F has a propensity to trigger upon exposure to elevated temperatures [28] and hypo-osmotic conditions [29] , and RSV F has even been shown to spontaneously trigger and refold over time due to the metastable nature of the prefusion conformation [30] . This raises the possibility that RSV F does not have a specific receptor that initiates triggering and fusion, but rather that spontaneous triggering in the presence of attachment factors, such as heparan sulfate proteoglycans [31] , is sufficient for entry.