Herpes Simplex virus (HSV) causes several serious human diseases including a sexually transmitted disease that significantly effects maternal and child health and may be a cofactor in the acquisition of other STDs such as AIDS. Once infected with HSV, individuals retain the virus in a latent state, from which periodic reactivation causes recurrent disease and provides an opportunity for transmission. The means to protect against HSV infection by inducing potent immune responses that can act quickly at the site of infection remains elusive. Replication-defective mutants of HSV offer a safer alternative to live virus vaccines. Because the infection does not spread in the host, these viruses also provide a unique tool to examine the induction of antiviral immune responses. Mice immunized subcutaneously or intranasally with an HSV-2 mutant virus generate immune responses that protect mice from disease and lethal infection upon genital challenge with a heterologous HSV-2 strain. It is hypothesized that immunization with replication-defective HSV-2 generates an immune response protective against genital HSV-2 that is principally mediated by CD4+ Th1 cells. In addition, it is also hypothesized that the provision of B7 co-stimulatory molecules in infected cells will augment the immunogenicity of the replication-defective virus and improve protective capacity.
In Aim 1, histochemical analysis of the vaginal mucosa and the analysis of latent genomes in the ganglia will identify the stage of pathogenesis that is blocked by the protective immune response.
In Aim 2, the components of the immune response that are protective against genital challenge will be identified using knockout mice, T cell subset depletions, and cytokine analyses.
In Aim 3, the role of costimulation in the induction of immune response to replication-defective virus will be investigated by construction of recombinant viruses that encode B7 molecules. This information will facilitate developent of immunization strategies against HSV and possibly other pathogens of the genital tract.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29CA075052-02
Application #
2896074
Study Section
Virology Study Section (VR)
Program Officer
Wong, May
Project Start
1998-04-01
Project End
2003-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Morrison, Lynda A (2008) Replication-defective virus vaccine-induced protection of mice from genital herpes simplex virus 2 requires CD4 T cells. Virology 376:205-10
Thebeau, Lydia G; Vagvala, Sri P; Wong, Yee M et al. (2007) B7 costimulation molecules expressed from the herpes simplex virus 2 genome rescue immune induction in B7-deficient mice. J Virol 81:12200-9
Duerst, Rebecca J; Morrison, Lynda A (2007) Herpes simplex virus type 2-mediated disease is reduced in mice lacking RNase L. Virology 360:322-8
Duerst, Rebecca J; Morrison, Lynda A (2004) Herpes simplex virus 2 virion host shutoff protein interferes with type I interferon production and responsiveness. Virology 322:158-67
Geiss, Brian J; Cano, Gina L; Tavis, John E et al. (2004) Herpes simplex virus 2 VP22 phosphorylation induced by cellular and viral kinases does not influence intracellular localization. Virology 330:74-81
Duerst, Rebecca J; Morrison, Lynda A (2003) Innate immunity to herpes simplex virus type 2. Viral Immunol 16:475-90
Thebeau, Lydia G; Morrison, Lynda A (2003) Mechanism of reduced T-cell effector functions and class-switched antibody responses to herpes simplex virus type 2 in the absence of B7 costimulation. J Virol 77:2426-35
Murphy, Jenny A; Duerst, Rebecca J; Smith, Tracy J et al. (2003) Herpes simplex virus type 2 virion host shutoff protein regulates alpha/beta interferon but not adaptive immune responses during primary infection in vivo. J Virol 77:9337-45
Keadle, Tammie L; Laycock, Keith A; Morris, Jessica L et al. (2002) Therapeutic vaccination with vhs(-) herpes simplex virus reduces the severity of recurrent herpetic stromal keratitis in mice. J Gen Virol 83:2361-5
Morrison, Lynda A (2002) Vaccines against genital herpes: progress and limitations. Drugs 62:1119-29

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