Acute and recurrent genital herpes remains a major health concern. In this application we propose to investigate the immune response to a number of HSV-2 polypeptides. We will then correlate these responses to the natural history of genital HSV-2 disease. We will also induce immunity to selected HSV-2 proteins prior to intravaginal challenge to examine the subsequent alterations in the natural history of the disease and also to boost selected responses after latency has been established to determine the consequences on recurrent HSV-2 infection. We have chosen to perform these evaluations using the guinea pig model of genital herpes because intravaginal HSV-2 inoculation of guinea pigs produces a self-limited genital disease and a latent infection in neural tissues. Unlike other small animal models, guinea pigs, however, also develop spontaneous clinically apparent recurrences that can also be induced by UV exposure. This unique model in inbred and outbred animals can, therefore, be used to evaluate the effects of immune intervention on virological and clinical manifestations of acute, recurrent and latent HSV-2 infections. We will develop vaccinia recombinants expressing selected HSV-2 polypeptides in order to induce immune responses to the selected HSV-2 polypeptides. We have chosen vaccinia because it has a wide host range and can incorporate large fragments of foreign DNA which are correctly processed in host cells. Further, inoculation with vaccinia can induce antibody and cell mediated immune functions, including cytotoxic T lymphocytes, to the foreign gene product. The polypeptides we will evaluate were selected because preliminary evidence with herpes viruses as well as other viruses suggests that these may be important antigens for antibody and especially cell mediated immunity. They include immediate early HSV-2 proteins, internal structural proteins, nonstructural proteins and glycoprotein C. The vaccinia recombinants developed as part of this application will also be used to make antigen and targets for antibody mediated immunity including immunoblot, ELISA and antibody dependent cellular cytotoxicity (ADCC) and cell mediated immunity including proliferation, and IL-2 as well as HSV specific MHC unrestricted (NK) and MHC restricted (CTL) assays. The overall goal of this proposal is to expand our understanding of the immune response to selected HSV polypeptides and their effects on acute and recur- rent genital herpes. This knowledge should ultimately provide new approaches to the control of this common public health problem.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023482-07
Application #
3135650
Study Section
Experimental Virology Study Section (EVR)
Project Start
1987-01-01
Project End
1996-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost
Name
James N. Gamble Institute of Medical Research
Department
Type
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45219
Milligan, G N; Bernstein, D I (1997) Interferon-gamma enhances resolution of herpes simplex virus type 2 infection of the murine genital tract. Virology 229:259-68
Bourne, N; Stanberry, L R; Bernstein, D I et al. (1996) DNA immunization against experimental genital herpes simplex virus infection. J Infect Dis 173:800-7
Bourne, N; Milligan, G N; Schleiss, M R et al. (1996) DNA immunization confers protective immunity on mice challenged intravaginally with herpes simplex virus type 2. Vaccine 14:1230-4
Milligan, G N; Bernstein, D I (1995) Generation of humoral immune responses against herpes simplex virus type 2 in the murine female genital tract. Virology 206:234-41
Bernstein, D I; Harrison, C J; Tepe, E R et al. (1995) Effect of imiquimod as an adjuvant for immunotherapy of genital HSV in guinea-pigs. Vaccine 13:72-6
Harrison, C J; Miller, R L; Bernstein, D I (1994) Posttherapy suppression of genital herpes simplex virus (HSV) recurrences and enhancement of HSV-specific T-cell memory by imiquimod in guinea pigs. Antimicrob Agents Chemother 38:2059-64
Bernstein, D I; Miller, R L; Harrison, C J (1993) Effects of therapy with an immunomodulator (imiquimod, R-837) alone and with acyclovir on genital HSV-2 infection in guinea-pigs when begun after lesion development. Antiviral Res 20:45-55
McLean, J H; Shipley, M T; Bernstein, D I et al. (1993) Selective lesions of neural pathways following viral inoculation of the olfactory bulb. Exp Neurol 122:209-22
Connelly, B L; Stanberry, L R; Bernstein, D I (1993) Detection of varicella-zoster virus DNA in nasopharyngeal secretions of immune household contacts of varicella. J Infect Dis 168:1253-5
Bernstein, D I; Miller, R L; Harrison, C J (1993) Adjuvant effects of imiquimod on a herpes simplex virus type 2 glycoprotein vaccine in guinea pigs. J Infect Dis 167:731-5

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