Herpes simplex viruses (HSVs) cause human diseases, including cold sores, eye and genital infections, ? Neo-natal infections and encephalitis. They establish lifelong latent infections within sensory ganglia. The HSV envelope contains 11 virus-encoded glycoprotein's of which 4 (gD, gB and the gH-gL complex) are essential for entry. Our challenge is to define the HSV fusion machinery and determine the role of the viral and cell proteins in this process. Although it is well established that gD binds to one of several different cellular receptors, the functions of the other 3 proteins is still elusive. It is generally hypothesized that gH/gL and/or gB carry out fusion of the viral envelope with host membranes, as a consequence of gD binding to receptor. We propose 3 specific aims: 1) to further characterize gD structure and its relationship to virus entry; 2) to explore the steps of virus entry that occur after gD binds its cell receptor; and 3} to carry out structure-function studies of HSV gH/gL. When gD binds HVEM, it undergoes two conformational changes as revealed by crystallographic data obtained during the previous application period. Since the C-terminal portion of the ectodomain was disordered in the crystal, it is possible that other changes occur. We hypothesize that at least one of these changes plays a role in later steps of entry. In addition, the two proteins co-crystallized as monomers and we know that each is normally oligomeric. In collaboration with Dr. A. Carfi, we solved the structure of an artificially stabilized form of dimeric gD. Though its structure fits many of our previous predictions, experiments are proposed to verify the structure and to use it for future studies.
In Aim 2, we will address the following question: how does the interaction between gD and its receptor trigger downstream events that lead to virus-cell fusion? It is known that HSV enters cells by at least two different mechanisms depending on the cell type. We have preliminary evidence for a third pathway that we plan to explore.
In Aim 3, we will collaborate with Dr. S. Harrison to solve the structure of gH/gL as part of our long term goal to elucidate the structure of all the HSV entry glycoproteins. Other experiments will address the function of gH/gL from both serotypes to augment the structural data and complement studies in Aims 1 and 2. The knowledge gained from these studies should contribute to our understanding of HSV entry and suggest new therapeutic approaches. ? ? ?

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-IDM-G (02))
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Beisel, Christopher E
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University of Pennsylvania
Schools of Dentistry
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Cairns, Tina M; Huang, Zhen-Yu; Gallagher, John R et al. (2015) Patient-Specific Neutralizing Antibody Responses to Herpes Simplex Virus Are Attributed to Epitopes on gD, gB, or Both and Can Be Type Specific. J Virol 89:9213-31
Saw, Wan Ting; Matsuda, Zene; Eisenberg, Roselyn J et al. (2015) Using a split luciferase assay (SLA) to measure the kinetics of cell-cell fusion mediated by herpes simplex virus glycoproteins. Methods 90:68-75
Cairns, Tina M; Huang, Zhen-Yu; Whitbeck, J Charles et al. (2014) Dissection of the antibody response against herpes simplex virus glycoproteins in naturally infected humans. J Virol 88:12612-22
Gallagher, John R; Atanasiu, Doina; Saw, Wan Ting et al. (2014) Functional fluorescent protein insertions in herpes simplex virus gB report on gB conformation before and after execution of membrane fusion. PLoS Pathog 10:e1004373
Whitbeck, J Charles; Huang, Zhen-Yu; Cairns, Tina M et al. (2014) Repertoire of epitopes recognized by serum IgG from humans vaccinated with herpes simplex virus 2 glycoprotein D. J Virol 88:7786-95
Cairns, Tina M; Fontana, Juan; Huang, Zhen-Yu et al. (2014) Mechanism of neutralization of herpes simplex virus by antibodies directed at the fusion domain of glycoprotein B. J Virol 88:2677-89
Lazear, Eric; Whitbeck, J Charles; Zuo, Yi et al. (2014) Induction of conformational changes at the N-terminus of herpes simplex virus glycoprotein D upon binding to HVEM and nectin-1. Virology 448:185-95
Atanasiu, Doina; Cairns, Tina M; Whitbeck, J Charles et al. (2013) Regulation of herpes simplex virus gB-induced cell-cell fusion by mutant forms of gH/gL in the absence of gD and cellular receptors. MBio 4:
Maurer, Ulrike E; Zeev-Ben-Mordehai, Tzviya; Pandurangan, Arun Prasad et al. (2013) The structure of herpesvirus fusion glycoprotein B-bilayer complex reveals the protein-membrane and lateral protein-protein interaction. Structure 21:1396-405
Gallagher, John R; Saw, Wan Ting; Atanasiu, Doina et al. (2013) Displacement of the C terminus of herpes simplex virus gD is sufficient to expose the fusion-activating interfaces on gD. J Virol 87:12656-66

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