Herpesviruses enter cells by fusing their envelopes with the host membrane. While most enveloped viruses use a single viral protein, all herpesviruses inexplicably require multiple proteins. We have determined the structures of key herpesvirus penetration proteins, gB and gH/gL complex, and identified gB as the fusogen and gH/gL as a uniquely folded regulator. These findings upended the established way of thinking about the functions of these proteins and enabled a mechanistic exploration of herpesvirus entry. However, many aspects of herpesvirus-mediated fusion and entry remain undefined. What does gB look like in its active, prefusion form? How does gB catalyze membrane fusion? How is it triggered by other glycoproteins? How do multiple herpesviral glycoproteins work together to bring about membrane fusion? Answering these questions may explain the unique features of the herpesvirus entry machinery. In addition to dissecting the membrane fusion mechanism of HSV-1, we also strive to understand how and why herpesviruses choose different cell entry routes depending on the host cell type. We will use a combination of structural biology, biophysics, and cell biology to obtain answers to these and other outstanding questions in the field of herpesvirus entry. The proposed studies will provide fundamental structural and mechanistic insights into gB-mediated membrane fusion and entry that are currently lacking and may challenge some of the existing paradigms.
Image from Wang et al., PNAS (2007)