Human studies suggest that acquired immune responses modify congenital cytomegalovirus (CMV)-induced disease. In these studies we will explore the roles of maternal, fetal, and neonatal immune responses to the pathogenesis of congenital CMV infection, employing the well-defined guinea pig CMV model which simulates human congenital infection. We will first perform detailed longitudinal in vitro studies of cell-mediated immune capabilities in each trimester and postpartum using blood and spleen cells obtained during normal uninfected guinea pig pregnancy. We will investigate proliferative responses to mitogens and to alloantigens, the later being major histocompatibility complex (MHC) Class II restricted. We will also study cytotoxic responses in uninfected pregnant animals and their fetuses/neonates as to endogenous MHC-unrestricted natural killer (NK) cell and antibody-dependent cell-mediated cytotoxicity (ADCC). Having defined the immune capabilities in uninfected pregnancy, we will then define perturbations and acquisition of immune responses in pregnant animals and their fetuses during infection with guinea pig CMV in each trimester. Confirmation of the extent of infection will be carried out by use of both viral culture and DNA hybridization techniques. Cell-mediated immune parameters to be investigated include proliferative responses to mitogens, alloantigen and CMV antigen, and cytotoxic responses (NK, ADCC, and MHC class I restricted cytotoxic T-lymphocyte assays). Since antibody may modify CMV disease expression, we will also examine humoral immune responses by plaque neutralization, by class (IgG, IgA, and IgM) using ELISA, and to specific CMV antigens by immunoblot technique. Comparisons of immune responses to infection acquired during each trimester will be correlated with rates and extent of transplacental infection and the outcome of pregnancy. Using the same techniques and immune assays, we will also compare immune responses and rates of transplacental infection during pregnancies that occur after recovery from virulent salivary derived guinea pig CMV infection to those of pregnancies after recovery from attenuated multiple tissue passaged guinea pig CMV.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Experimental Virology Study Section (EVR)
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Cincinnati Children's Hospital Medical Center
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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
Harrison, C J; Burger, R (1991) Low maternal CD4 count at inception of gestational cytomegalovirus (CMV) infection and impaired humoral response: effect on congenital CMV infection in the guinea pig. Clin Immunol Immunopathol 60:171-80
Bernstein, D I; Harrison, C J; Jenski, L J et al. (1991) Cell-mediated immunologic responses and recurrent genital herpes in the guinea pig. Effects of glycoprotein immunotherapy. J Immunol 146:3571-7
Stanberry, L R; Harrison, C J; Bravo, F J et al. (1990) Recurrent genital herpes in the guinea pig augmented by ultraviolet irradiation: effects of treatment with acyclovir. Antiviral Res 13:227-35
Kacica, M A; Harrison, C J; Myers, M G et al. (1990) Immune response to guinea pig cytomegalovirus polypeptides and cross reactivity with human cytomegalovirus. J Med Virol 32:155-9
Harrison, C J; Myers, M G (1990) Relation of maternal CMV viremia and antibody response to the rate of congenital infection and intrauterine growth retardation. J Med Virol 31:222-8
Stanberry, L R; Harrison, C J; Bernstein, D I et al. (1989) Herpes simplex virus glycoprotein immunotherapy of recurrent genital herpes: factors influencing efficacy. Antiviral Res 11:203-14
Bernstein, D I; Harrison, C J (1989) Effects of the immunomodulating agent R837 on acute and latent herpes simplex virus type 2 infections. Antimicrob Agents Chemother 33:1511-5
Harrison, C J; Myers, M G (1989) Maternal cell-mediated cytolysis of CMV-infected fetal cells and the outcome of pregnancy in the guinea pig. J Med Virol 27:66-71
Myers, M G; Bernstein, D I; Harrison, C J et al. (1988) Herpes simplex virus glycoprotein treatment of recurrent genital herpes reduces cervicovaginal virus shedding in guinea pigs. Antiviral Res 10:83-8

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