Structure and function of HCMV gHgL complexes

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Human cytomegalovirus (HCMV) is member of the herpesvirus family that is widely distributed in the human population and responsible for significant health problems, particularly in immune-compromised individuals and in newborns exposed to the virus during pregnancy or birth. Understanding the immune response to HCMV infection, and in particular the major targets of the neutralizing antibody response, is of great interest as efforts to develop an effective vaccine are of high priority. Recent studies have shown that one of the most potent targets of the neutralizing antibody response is an assembly of 5 HCMV glycoproteins, gH, gL, UL128, UL130 and UL131, into a `pentameric' complex, which is responsible for broadening the infectivity of the virus to endothelial, epithelial and myeloid cells. The gH and gL proteins are part of the core herpesvirus membrane fusion and entry machinery, while the UL proteins represent virus-specific adaptors that modulate cell tropism. Low resolution electron microscopy studies of HCMV gHgL, pentamer and antibody complexes have been reported, providing insight into the overall shape of the pentamer and the locations of neutralizing antibody epitopes. However, no high resolution structures have been determined, limiting our insights into the overall folding and architecture of the gHgL pentamer as well as the relationship between neutralizing antibody epitopes and neutralization potency. Here we will determine the structures of HCMV pentamer in complex with representative neutralizing antibodies. In addition, we will map key gHgL and UL protein residues involved in pentamer assembly, antibody binding and gHgL functions, using cell surface library display approaches. Results generated from this proposal will deepen our understanding of the HCMV entry machinery, facilitate the identification of HCMV entry receptors, and provide key fundamental knowledge for the development of vaccine antigens and small molecule inhibitors to prevent HCMV infection.