Herpes simplex viruses (HSVs) cause human diseases, including cold sores, eye and genital infections, neonatal infections and encephalitis. HSVl and HSV2 establish lifelong latent infections within sensory ganglia and recurrent infections are common. Many people in the U.S. and worldwide are infected by one or both serotypes of HSV and there is increasing evidence that HSV2 infections contribute to the spread of HIV. HSV remains a major human pathogen worldwide, causing cold sores, eye and genital infections, blindness, encephalitis, and neonatal infections. After infection, glycoproteins are expressed on the cellular membranes and are major targets ofthe host's immune response. The virus envelope contains eleven glycoproteins that are important for infection and pathogenesis. Our long term objective is to understand the mechanisms by which HSV glycoproteins interact with each other and with cell molecules to mediate HSV entry into mammalian cells. Four glycoproteins, gD, gB and a complex of gH/gL are essential for virus entry. Glycoprotein D, a structural component ofthe HSV envelope is necessary for the stable binding of the virus with receptors on cells as well as fusion ofthe virus envelope with the plasma membrane. Virus entry is triggered first by the interaction between gD and one of its receptors. This interaction then triggers downstream events that necessarily involve the core fusion machinery consisting of gB and gH/gL. An important question is: how does the interaction between gD and it(s) receptor trigger action by gB and gH/gL to cause fusion? Our approach to answering this complex question has been to study the structure and function of both the virion glycoproteins and receptors. Therefore, we propose three 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 gH/gL of HSVl and HSV- 2. Our studies should provide information about the specific steps of HSV entry and have significance for the herpesvirus field as well as for the larger field of virus entry. On a more practical level, our findings should find application for development of vaccines and new therapeutics against HSVl and HSV2.

Public Health Relevance

Infections caused by herpes simplex viruses remain major health problems in the U.S. The genital form, HSV2 facilitates spread of HIV-AIDS. An effective vaccine against HSV2 is urgently needed. HSV uses 4 proteins, gB, gD and a gH/gL complex to invade cells. We will study how they work together and how the host responds with the long term goal of making effective vaccines and new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI018289-32
Application #
8468088
Study Section
Special Emphasis Panel (NSS)
Program Officer
Challberg, Mark D
Project Start
1981-09-30
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
32
Fiscal Year
2013
Total Cost
$366,748
Indirect Cost
$134,098
Name
University of Pennsylvania
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
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
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Atanasiu, Doina; Saw, Wan Ting; Gallagher, John R et al. (2013) Dual split protein-based fusion assay reveals that mutations to herpes simplex virus (HSV) glycoprotein gB alter the kinetics of cell-cell fusion induced by HSV entry glycoproteins. J Virol 87:11332-45
Krummenacher, Claude; Carfi, Andrea; Eisenberg, Roselyn J et al. (2013) Entry of herpesviruses into cells: the enigma variations. Adv Exp Med Biol 790:178-95
Lazear, Eric; Whitbeck, J Charles; Ponce-de-Leon, Manuel et al. (2012) Antibody-induced conformational changes in herpes simplex virus glycoprotein gD reveal new targets for virus neutralization. J Virol 86:1563-76

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