Herpes simplex virus type 2 (HSV-2) is a pathogenic agent that is associated with serious public health problems including HIV-1 acquisition and over one million new cases of genital herpes per year in the US. Current methods to control HSV-2 including antiviral drugs, education, and barrier methods are inadequate, and the prevalence of HSV-2 infection is steadily increasing. The long-term goal of this proposal is to design an effective prophylactic HSV-2 vaccine. Several lines of evidence indicate the HSV-2-specific CD8 T-cell responses may be important in controlling the severity of HSV-2 infection. Little is known concerning the identity of the immunodominant HSV-2 antigens recognized by CD8 T-cells. Based upon the mechanisms of action of action of HSV-2-encoded immune evasion genes, and upon empiric data, we hypothesize that proteins in the viral tegument, which are injected into the cell during viral entry, and HSV-2 proteins that are synthesized shortly after infection, are the immunodominant CD8 antigens of HSV-2. We will test this hypothesis using assays that measure CD8 T-cell responses to defined HSV-2 antigens and peptides. The expression of a skin-homing receptor by HSV-2-specific CD8 T-cells will be used to both purify CD8 CTL for a short interval to finish antigen discovery, and also to enrich polyclonal HSV-2-specific CTL for these assays. The primary readouts, ELISPOT, CTL, and tetramer assays, will be used to rank HSV-2 antigens in a hierarchy of immunodominance. To focus resources, analysis of subjects with asymptomatic HSV-2 infection, low HSV-2 shedding rates, and the prevalent HLA A*0201 allele will be emphasized. We further hypothesize that variations in CD8 T-cell responses to HSV-2 may be associated with disease HSV-2 severity. To test this hypothesis, we will characterize study subjects with HLA A*0201 and severe, symptomatic HSV-2 infection, and compare HSV-2-specific CD8 responses between persons with mild and severe infection. Assays will focus on responses to the HSV-2 antigens found to be immunodominant in HLA A*0201-bearing persons with asymptomatic infection. If our hypotheses is correct, we will have identified HSV-2 antigens that are rational components of a future generation HSV-2 vaccine, and will have a strong rational with development of a prophylactic or therapeutic vaccination format that will be elicit HSV-2-specific CD8 responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050132-05
Application #
7171865
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
David, Hagit S
Project Start
2003-02-15
Project End
2009-01-31
Budget Start
2007-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2007
Total Cost
$251,553
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Marshak, Joshua O; Dong, Lichun; Koelle, David M (2014) The murine intravaginal HSV-2 challenge model for investigation of DNA vaccines. Methods Mol Biol 1144:305-27
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Laing, Kerry J; Magaret, Amalia S; Mueller, Dawn E et al. (2010) Diversity in CD8(+) T cell function and epitope breadth among persons with genital herpes. J Clin Immunol 30:703-22
Dong, Lichun; Li, Penny; Oenema, Tjitske et al. (2010) Public TCR use by herpes simplex virus-2-specific human CD8 CTLs. J Immunol 184:3063-71
Muller, William J; Dong, Lichun; Vilalta, Adrian et al. (2009) Herpes simplex virus type 2 tegument proteins contain subdominant T-cell epitopes detectable in BALB/c mice after DNA immunization and infection. J Gen Virol 90:1153-63
Zhu, Jia; Hladik, Florian; Woodward, Amanda et al. (2009) Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat Med 15:886-92
Diaz, George A; Koelle, David M (2006) Human CD4+ CD25 high cells suppress proliferative memory lymphocyte responses to herpes simplex virus type 2. J Virol 80:8271-3
Koelle, David M; Huang, Jay; Hensel, Michael T et al. (2006) Innate immune responses to herpes simplex virus type 2 influence skin homing molecule expression by memory CD4+ lymphocytes. J Virol 80:2863-72
Koelle, David M; Gonzalez, Julio C; Johnson, Andrew S (2005) Homing in on the cellular immune response to HSV-2 in humans. Am J Reprod Immunol 53:172-81
Diaz, George A; Rakita, Robert M; Koelle, David M (2005) A case of Ramsay Hunt-like syndrome caused by herpes simplex virus type 2. Clin Infect Dis 40:1545-7

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