The natural history of herpes simplex type II genital infection in guinea pigs is similar to human disease. After intravaginal inoculation animals develop a self-limited genital infection, establish latent infection and later exhibit spontaneous symptomatic, as well as subclinical recurrent disease. These aspects of HSV infection can be quantified by clinical illness score, virus plaque titration, explant cocultivation and HSV DNA hybridization. Utilizing this well characterized model of genital HSV2 disease we propose to evaluate immune functions that may alter the acute infection or modify the recurrence pattern. To accomplish these goals we have developed assays for HSV specific cell-mediated immune functions including natural killer (NK) cell cytotoxicity, antibody dependent cell cytotoxicity (ADCC), lymphocyte blastogenesis or delayed hypersensitivity as well as humoral immunity including neutralizing, ADCC, and antibody to specific HSV polypeptides. In addition we are developing assays to evaluate the cytotoxic t cell activity. We will take advantage of the variable severity of the acute disease in outbred Hartley guinea pigs as well as age and strain related differences to investigate immune factors that could account for these differences. Similarly, we will use the variable recurrence patterns that develop in outbred Hartley animals and the markedly lower (compared to Hartley animals) recurrence pattern in strain 2 guinea pigs to examine immune characteristics that might influence the pattern of recurrent disease. We will determine the recurrence pattern in strain 13 and DHCBA strain animals which will allow the exploration of relationship between class I and class II guinea pig lymphocyte antigen (GPLA) complex and the recurrence pattern. Because a guinea pig can be bled repetitively we will be able to follow the development of specific immune functions and relate these to periods of quiescence or recurrences in the same animal. The zosteriform model of genital herpes we have developed allows anatomic separation of the various stages of initial genital infection and will enable investigation of the ability of passively acquired antibody or specific immune cells to modify infection at several sites in the same animal. We will also utilize a subunit HSV glycoprotein vaccine and a model of HSV1 oral infection to better define the site and mechanisms by which these may modify genital HSV2 infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Experimental Virology Study Section (EVR)
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James N. Gamble Institute of Medical Research
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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; 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
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
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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