Herpesviruses are associated with a variety of disease in the human host, ranging from asymptomatic infections to life threatening disease, including encephalitis and cancer. In addition to playing a direct role in cancer genesis, herpesviruses pose an increased risk to cancer patients who may develop debilitating and life- threatening herpesvirus infections. Genital herpes simplex virus (HSV) lesions, even if clinically inapparent, can facilitate the transfer of HIV-infected cells or free virus from one individual to another, and HIV infection and AIDS increase the risks of developing certain kinds of cancer. HSV-1 serves as a prototypic herpesvirus family member and provides an ideal model to understand the requirements for virus infection since it replicates well in cell culture and many reagents have been developed for its study. Herpesvirus entry into cells requires fusion of the outer envelope of the virus with a cell membrane. Spread of infection can occur via infectious virus or virus-induced cell fusion. The ultimate objective of studies described here is to understand how herpesviruses, specifically HSV-1, induce membrane fusion, the process required for viral entry and cell fusion. Requirements for HSV-induced membrane fusion include the coordinated activities of four HSV glycoproteins (gD, the hererodimeric gH/gL complex, and gB) and specific cellular receptors. Our central hypothesis is that gD, present in the viral envelope or on an infected cell surface, binds to a cellular receptor, such as nectin-1, on an uninfected cell and activates gH/gL and gB via protein-protein interactions resulting in fusion mediated by gB. In three aims, we plan to define the sequence requirements and domains contained on gD, gH/gL and gB that are required to mediate membrane fusion and to begin studies to solve the prefusion conformation of gB. The proposed studies will result in a better understanding of the basic mechanisms that are central to herpesvirus infection of cells and virus spread from cell-to-cell. The results of these studies will lead to an understanding of the mechanism of herpesvirus-induced membrane fusion and to new approaches for the prevention and treatment of herpesvirus infections.

Public Health Relevance

This proposed research will further define the molecular mechanisms involved in herpesvirus infection using the prototypic human herpesvirus herpes simplex virus 1 (HSV-1). Herpesviruses cause significant disease and morbidity within the human population ranging from asymptomatic infections and blindness to life threatening illness such as encephalitis and cancer. The proposed research may result in the identification of new therapeutics for herpesviruses that will lessen the pathologies associated with viral infection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA021776-34A1
Application #
8439972
Study Section
Virology - B Study Section (VIRB)
Program Officer
Daschner, Phillip J
Project Start
1977-09-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
34
Fiscal Year
2013
Total Cost
$267,575
Indirect Cost
$94,387
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Fan, Qing; Longnecker, Richard; Connolly, Sarah A (2014) Substitution of herpes simplex virus 1 entry glycoproteins with those of saimiriine herpesvirus 1 reveals a gD-gH/gL functional interaction and a region within the gD profusion domain that is critical for fusion. J Virol 88:6470-82
Zago, Anna; Connolly, Sarah A; Spear, Patricia G et al. (2013) The fusion loops and membrane proximal region of Epstein-Barr virus glycoprotein B (gB) can function in the context of herpes simplex virus 1 gB when substituted individually but not in combination. Virus Res 171:227-30
Fan, Qing; Bohannon, Kevin P; Longnecker, Richard (2013) Drosophila Schneider 2 (S2) cells: a novel tool for studying HSV-induced membrane fusion. Virology 437:100-9
Connolly, Sarah A; Jackson, Julia O; Jardetzky, Theodore S et al. (2011) Fusing structure and function: a structural view of the herpesvirus entry machinery. Nat Rev Microbiol 9:369-81
Fan, Qing; Longnecker, Richard (2010) The Ig-like v-type domain of paired Ig-like type 2 receptor alpha is critical for herpes simplex virus type 1-mediated membrane fusion. J Virol 84:8664-72
Jackson, Julia O; Lin, Erick; Spear, Patricia G et al. (2010) Insertion mutations in herpes simplex virus 1 glycoprotein H reduce cell surface expression, slow the rate of cell fusion, or abrogate functions in cell fusion and viral entry. J Virol 84:2038-46
Bieging, Kathryn T; Swanson-Mungerson, Michelle; Amick, Alexandra C et al. (2010) Epstein-Barr virus in Burkitt's lymphoma: a role for latent membrane protein 2A. Cell Cycle 9:901-8
Fan, Qing; Lin, Erick; Spear, Patricia G (2009) Insertional mutations in herpes simplex virus type 1 gL identify functional domains for association with gH and for membrane fusion. J Virol 83:11607-15
Wang, Jing; Fan, Qing; Satoh, Takeshi et al. (2009) Binding of herpes simplex virus glycoprotein B (gB) to paired immunoglobulin-like type 2 receptor alpha depends on specific sialylated O-linked glycans on gB. J Virol 83:13042-5
Aubert, Martine; Yoon, Miri; Sloan, Derek D et al. (2009) The virological synapse facilitates herpes simplex virus entry into T cells. J Virol 83:6171-83

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