Effective vaccines are not currently available for many agents including herpes simplex virus (HSV). One of the challenges of modern vaccinology is to design strategies that will sculpt the immune system to expand components which subserve a protective role and diminish activities which are potentially counterprotective. For optimal defence against HSV, it is probably necessary to maximize the CD8+ T cell and CD4+ Th1 cell subtype response since these components are crucial for prompt and effective viral clearance. Using in vitro systems optimal means of inducing HSV specific cytotoxic T lymphocyte (CTL) and CD4+ Th1 cell mediated response will be developed. As antigens, glycoprotein B and ICP27 proteins and some of their component peptides as well as DNA preparations encoding the protein and peptides, will be used. Culture conditions will be manipulated mainly with respect to the cytokine environment to achieve induction of immune responses dominated by different components of immunity. Optimal means of inducing protective immune responses in vivo against HSV with DNA vaccines will also be sought, and the nature of the immune response induced measured. The achievement of optical protective responses is hypothesized to require the delivery of candidate immunogens maximally to dendritic cells. It may also be necessary for the immunogen to have additional costimulator activity, such as IG-12 production, that will condition the local environment of the antigen presenting and responder T cells to generate mainly the Th1 subtype of CD4+ T cells. Several strategies for maximally inducing CD8+ and CD4+ Th1 HSV specific response will be evaluated and experiments will also be done to demonstrate the relative role of CD8+, CD4+ Th1 and CD4+ Th2 T cells in controlling HSV pathogenesis in mouse model systems. The findings should be relevant to the future development of vaccines that will successfully control HSV infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI014981-20
Application #
2671696
Study Section
Virology Study Section (VR)
Project Start
1978-05-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
20
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Tennessee Knoxville
Department
Microbiology/Immun/Virology
Type
Schools of Veterinary Medicine
DUNS #
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Suvas, Susmit; Kim, Bumseok; Rouse, Barry T (2008) Homeostatic expansion of CD4(+) T cells upregulates VLA-4 and exacerbates HSV-induced corneal immunopathology. Microbes Infect 10:1192-200
Rouse, Barry T; Kaistha, Shilpa Deshpande (2006) A tale of 2 alpha-herpesviruses: lessons for vaccinologists. Clin Infect Dis 42:810-7
Rouse, Barry T; Sarangi, Pranita P; Suvas, Susmit (2006) Regulatory T cells in virus infections. Immunol Rev 212:272-86
Suvas, Susmit; Rouse, Barry T (2006) Treg control of antimicrobial T cell responses. Curr Opin Immunol 18:344-8
Kumaraguru, Udayasankar; Banerjee, Kaustuv; Rouse, Barry T (2005) In vivo rescue of defective memory CD8+ T cells by cognate helper T cells. J Leukoc Biol 78:879-87
Suvas, Susmit; Kim, Bumseok; Sarangi, Pranita P et al. (2005) In vivo kinetics of GITR and GITR ligand expression and their functional significance in regulating viral immunopathology. J Virol 79:11935-42
Kumaraguru, Udayasankar; Suvas, Susmit; Biswas, Partha S et al. (2004) Concomitant helper response rescues otherwise low avidity CD8+ memory CTLs to become efficient effectors in vivo. J Immunol 172:3719-24
Toka, Felix N; Pack, Christopher D; Rouse, Barry T (2004) Molecular adjuvants for mucosal immunity. Immunol Rev 199:100-12
Toka, Felix N; Suvas, Susmit; Rouse, Barry T (2004) CD4+ CD25+ T cells regulate vaccine-generated primary and memory CD8+ T-cell responses against herpes simplex virus type 1. J Virol 78:13082-9
Suvas, Susmit; Azkur, Ahmet Kursat; Kim, Bum Seok et al. (2004) CD4+CD25+ regulatory T cells control the severity of viral immunoinflammatory lesions. J Immunol 172:4123-32

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