The objective of the proposed investigation is to carry out a detailed biochemical and immunological study of the type-common envelope glycoprotein D of herpes simplex virus (HSV) type l (oral form) and HSV-2 (genital form). Many structural and immunological properties of gD indicate that it is an important candidate for consideration as a subunit vaccine. We plan to localize, construct and characterize antigenic determinants of gD. We will characterize monoclonal antibodies from a number of laboratories in an effort to identify additional gD epitopes. Antibodies will be tested against a variety of fragments derived from gD, to facilitate mapping. In addition, synthetic peptides corresponding to the probable locations of specific epitopes will be synthesized and tested for antigenicity production of neutralizing antibody, and ability to stimulate a protective immune response in mice. Monoclonal antibody resistant (mar) mutants will be analyzed in an effort to further localize gD epitopes. Experiments are proposed to determine the number and location of disulfide bridges in gD-l and gD-2. These studies will be of importance in understanding aspects of the secondary and tertiary structure of gD. These structural studies will enable us to understand the nature of conformational epitopes. Preparations of gD-l and gD-2 and fragments derived from these proteins will be evaluated for their protective capacity in a mouse virus challenge model system. We will assess the relationship between stimulation of neutralizing antibody and protection against lethal virus challenge. The studies proposed in this grant will permit an assessment to be made of the usefulness of glycoprotein D or a derivative of it in stimulating a protective immune response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI018289-07
Application #
3127814
Study Section
Virology Study Section (VR)
Project Start
1981-09-30
Project End
1989-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Dentistry/Oral Hygn
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Atanasiu, Doina; Saw, Wan Ting; Lazear, Eric et al. (2018) Using Antibodies and Mutants To Localize the Presumptive gH/gL Binding Site on Herpes Simplex Virus gD. J Virol 92:
Hook, Lauren M; Cairns, Tina M; Awasthi, Sita et al. (2018) Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs. PLoS Pathog 14:e1007095
Hensel, Michael T; Marshall, Jason D; Dorwart, Michael R et al. (2017) Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir. J Virol 91:
Cairns, Tina M; Ditto, Noah T; Lou, Huan et al. (2017) Global sensing of the antigenic structure of herpes simplex virus gD using high-throughput array-based SPR imaging. PLoS Pathog 13:e1006430
Fontana, Juan; Atanasiu, Doina; Saw, Wan Ting et al. (2017) The Fusion Loops of the Initial Prefusion Conformation of Herpes Simplex Virus 1 Fusion Protein Point Toward the Membrane. MBio 8:
Atanasiu, Doina; Saw, Wan Ting; Eisenberg, Roselyn J et al. (2016) Regulation of HSV glycoprotein induced cascade of events governing cell-cell fusion. J Virol :
Persson, Josefine; Zhang, Yuan; Olafsdottir, Thorunn A et al. (2016) Nasal Immunization Confers High Avidity Neutralizing Antibody Response and Immunity to Primary and Recurrent Genital Herpes in Guinea Pigs. Front Immunol 7:640
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

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