Approximately 1 in 5 Americans are infected with herpes simplex virus type 2 (HSV-2) and the approximate direct cost of genital HSV disease exceeds $200 million annually. In addition to the devastating effects of HSV infections in newborns, genital lesions caused by HSV represent a major risk factor for acquisition of HIV. The increased frequency of recurrent disease and the inability to resolve oral and anogenital HSV lesions remains a serious complication for many immunocompromised patients. There is no licensed vaccine for the prevention of HSV disease. Vaccines recently tested in clinical trial elicited high titers of specific antibody but did not protect all populations against HSV-2 infection. The proposed studies will focus on the protective responses by specific T cell subsets and examine the mechanisms by which they act in the genital epithelium, sensory ganglia, and spinal cord to resolve HSV infections.
In Aim 1, we will transfer HSV-immune CD4+ and CD8+ T cell populations to bone marrow chimeric mice to examine the role of epithelial cells, innate immune cells, and IFN-gamma in clearance of HSV from the genital tract. We will determine if the cellular targets for IFN-gamma are hemopoietic or somatic cells and examine the molecular mechanisms of IFN-gamma -mediated protection of this site. HSV-1 is also emerging as an important genital pathogen.
In Aim 2, we will identify the T cell subsets responsible for protection against genital HSV-1 infections. We will utilize ELISPOT and Tetramer staining to quantify recall T cell responses and assess their ability to protect the sensory ganglia following heterotypic genital HSV challenge.
In Aim 3, we will analyze the protective role of CD4+ T cells in neuronal tissue. We will use cell depletion and adoptive transfer experiments to test the dependence of the HSV-specific recall antibody response and neuronal CD8+ T cell response on CD4+ T cells. Additionally, we will utilize adoptive transfer of immune CD4+ T cells to immunodeficient mice to determine if CD4+ T cells contribute to HSV clearance from neuronal tissue. The results of these studies should be important for the rational development of HSV vaccines as well as understanding the cellular interactions and specific molecular mechanisms required for resolution of HSV lesions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042815-09
Application #
7188102
Study Section
Experimental Virology Study Section (EVR)
Program Officer
Hiltke, Thomas J
Project Start
1999-02-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
9
Fiscal Year
2007
Total Cost
$250,557
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Nelson, Michelle H; Bird, Melanie D; Chu, Chin-Fun et al. (2011) Rapid clearance of herpes simplex virus type 2 by CD8+ T cells requires high level expression of effector T cell functions. J Reprod Immunol 89:10-7
Johnson, Alison J; Nelson, Michelle H; Bird, Melanie D et al. (2010) Herpes simplex virus (HSV)-specific T cells activated in the absence of IFN-gamma express alternative effector functions but are not protective against genital HSV-2 infection. J Reprod Immunol 84:8-15
Johnson, Alison J; Chu, Chin-Fun; Milligan, Gregg N (2008) Effector CD4+ T-cell involvement in clearance of infectious herpes simplex virus type 1 from sensory ganglia and spinal cords. J Virol 82:9678-88
Chu, Chin-Fun; Meador, Michael G; Young, Christal G et al. (2008) Antibody-mediated protection against genital herpes simplex virus type 2 disease in mice by Fc gamma receptor-dependent and -independent mechanisms. J Reprod Immunol 78:58-67
Bird, Melanie D; Chu, Chin-Fun; Johnson, Alison J et al. (2007) Early resolution of herpes simplex virus type 2 infection of the murine genital tract involves stimulation of genital parenchymal cells by gamma interferon. J Virol 81:423-6
Milligan, Gregg N; Meador, Michael G; Chu, Chin-Fun et al. (2005) Long-term presence of virus-specific plasma cells in sensory ganglia and spinal cord following intravaginal inoculation of herpes simplex virus type 2. J Virol 79:11537-40
Milligan, Gregg N; Young, Christal G; Meador, Michael G et al. (2005) Effects of candidate vaginally-applied microbicide compounds on innate immune cells. J Reprod Immunol 66:103-16
Dobbs, Melanie E; Strasser, Jane E; Chu, Chin-Fun et al. (2005) Clearance of herpes simplex virus type 2 by CD8+ T cells requires gamma interferon and either perforin- or Fas-mediated cytolytic mechanisms. J Virol 79:14546-54
Milligan, Gregg N; Dudley-McClain, Kristen L; Young, Christal G et al. (2004) T-cell-mediated mechanisms involved in resolution of genital herpes simplex virus type 2 (HSV-2) infection of mice. J Reprod Immunol 61:115-27
Milligan, Gregg N; Chu, Chin-Fun; Young, Christal G et al. (2004) Effect of candidate vaginally-applied microbicide compounds on recognition of antigen by CD4+ and CD8+ T lymphocytes. Biol Reprod 71:1638-45

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