Herpesvirus entry

Herpesvirus entry into cells

To gain access to cell cytosol, all viruses must breach cell membrane. Herpesviruses enter cells by fusing their envelopes with the host membrane using a complex, poorly understood mechanism. While most enveloped viruses use a single viral protein to effect cell entry, all herpesviruses require at least three conserved proteins: gB, gH, and gL, plus other non-conserved proteins, e.g., HSV gD. This level of complexity is remarkable in viruses, posing a question virologists have asked for several decades: why do herpesviruses need several proteins to effect entry? The answer to this question has important implications for the design of vaccines and therapeutics to prevent entry. We now know that in herpesviruses, the receptor- binding and the fusogenic functions are distributed among multiple proteins. The mechanistic details are best understood for Herpes Simplex viruses Type 1 and 2 (HSV-1 and HSV-2). Binding of gD, the receptor-binding protein, to its cellular receptors nectin-1 or herpesvirus entry mediator (HVEM) is thought to trigger the conserved membrane fusion machinery composed of gB and gH/gL. Receptor-bound gD probably interacts with and activates gH/gL, which in turn, is thought to interact with and activate gB. We were the first to succeed in solving the structures of gB and gH/gL of HSV, which revealed that gB is a viral fusogen and gH/gL, a fusion activator. We are working to determine the atomic-level mechanism by which these viral proteins mediate viral entry and cell-cell fusion of infected cells. We are interested in identifying both the conserved and virus-specific features of this mechanism. Our ambition is to develop a “molecular movie” illustrating the entry of herpesviruses into cells.