Doctoral Dissertations

Date of Award

12-1997

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Barry T. Rouse

Committee Members

Albert T. Ichiki, Robert N. Moore, Philip Bochsler, Joyce, Merryman

Abstract

This study was designed to explore different mucosal immunization strategies for inducing immunity to HSV and, additionally, to understand the immunological mechanisms protecting against vaginal Herpes Simplex Virus (HSV) infection. Initially, we demonstrated that intranasal administration of naked DNA expressing foreign genes resulted in mRNA and protein expression in the lung and the local draining lymph nodes. Additionally, mucosal administration of plasmid DNA encoding glycoprotein B (gB) of HSV not only generated systemic immunity but was also able to induce distal mucosal immune responses in the vaginal tract engaging the common mucosal immune system. The efficacy of this immunization strategy was evaluated using mucosal as well as systemic HSV challenge models. These novel observations set the stage for the design of future studies using the mucosal cytokine gene delivery strategy not to induce but rather to modulate the immunity to HSV at mucosal sites.

The second part of this work demonstrates the ability of replication defective HSV (ICP4-/-) but not UV HSV to induce mucosal immunity and protection when given enterically to naive animals. Interestingly, nonreplicating rHSV engineered to express TH1 (IFNγ) or TH2 (IL4) cytokines delivered by the same route were able to modulate local and systemic immunity.

Finally, we provided evidence that intranasal immunization with VgB or VgD, although generating strong vaginal antibodies, was insufficient to prevent initial infection and that protection against vaginal infection is a function of CD4 T cell responses. Our results suggest that future vaccines should be designed to generate a strong T cell immunity, thus preventing disease expression rather then preventing initial viral infection.

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