We have defined three profound defects regarding the ability of neonatal humans and mice to respond to herpes simplex virus (HSV) infection. These include 1) an inability to destroy viral- infected cells in the presence of antibody (antibody-dependent cellular cytotoxicity-ADCC) in vitro, 2) a related defect in the inability of human neonatal cells in the presence of antibody to protect neonatal mice from HSV infection, (ADCC in vitro, and 3) an inability to generate ADCC-mediating antiviral antibody after HSV challenge (a combined macrophage, T-lymphokine-dependent defect). We hypothesize that these ADCC antibody production and effector cell defects are central to the poor outcome of neonatal HSV infection. Reconstitution of these defects will change the mortality of HSV infection. These murine models act as in vivo """"""""test tubes"""""""" of human resistance factors against HSV infection. In this resubmitted proposal the murine and human antibody production defect will be further characterized (neutralization, ELISA), and the ontogeny of adult syngeneic T cell and macrophage reconstitution will be defined. The role of these cells and soluble replacing factors will be probed, with particular attention to human soluble factors from adults and neonates. Finally the antibody reconstitution will be correlated with survival. Preliminary experiments have demonstrated that both neonatal murine and human lymphocyte are unable to provide the necessary T-cell dependent lymphokine which reconstitutes antibody production and resistance to lethal neonatal HSV infection in combination with syngeneic macrophages. The ADCC effector defect will also be further characterized in vivo (human to mouse adoptive transfer) by analysis of the effector cell, the antibody type and target, the role of LFA- 1/OKM-1 adhesive glycoproteins, viral restriction, and finally the reconstitution of human neonatal effector function by stepwise immunomodulation o the adhesive and lytic defects. Both models (ADCC antibody production and effector cell reconstitution) will be extended from one of prophylaxis to one of therapy. Achievement of these goals of reconstitution of the neonatal defects will provide a logical step towards reduction of mortality of neonatal HSV infection in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI023247-02
Application #
3135134
Study Section
Experimental Virology Study Section (EVR)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Public Health
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Kohl, S (1991) Role of antibody-dependent cellular cytotoxicity in neonatal infection with herpes simplex virus. Rev Infect Dis 13 Suppl 11:S950-2
Kohl, S (1991) Role of antibody-dependent cellular cytotoxicity in defense against herpes simplex virus infections. Rev Infect Dis 13:108-14
Gateley, A; Gander, R M; Johnson, P C et al. (1990) Herpes simplex virus type 2 meningoencephalitis resistant to acyclovir in a patient with AIDS. J Infect Dis 161:711-5
Kohl, S; Strynadka, N C; Hodges, R S et al. (1990) Analysis of the role of antibody-dependent cellular cytotoxic antibody activity in murine neonatal herpes simplex virus infection with antibodies to synthetic peptides of glycoprotein D and monoclonal antibodies to glycoprotein B. J Clin Invest 86:273-8
Ashkenazi, M; Kohl, S (1990) Reduced antibody-dependent cellular cytotoxicity to herpes simplex virus-infected cells of salivary polymorphonuclear leukocytes and inhibition of peripheral blood polymorphonuclear leukocyte cytotoxicity by saliva. J Immunol 144:4781-7
Kohl, S (1990) A hypothesis on the pathophysiology of neonatal herpes simplex virus encephalitis: clinical recurrence after asymptomatic primary infection. Pediatr Infect Dis J 9:307-8
Kohl, S (1990) Protection against murine neonatal herpes simplex virus infection by lymphokine-treated human leukocytes. J Immunol 144:307-12
Oh, S H; Douglas, J M; Corey, L et al. (1989) Kinetics of the humoral immune response measured by antibody-dependent cell-mediated cytotoxicity and neutralization assays in genital herpesvirus infections. J Infect Dis 159:328-30
Kohl, S; West, M S; Prober, C G et al. (1989) Neonatal antibody-dependent cellular cytotoxic antibody levels are associated with the clinical presentation of neonatal herpes simplex virus infection. J Infect Dis 160:770-6
Kohl, S; Loo, L S; Rench, M A et al. (1989) Effect of intravenously administered immune globulin on functional antibody to herpes simplex virus in low birth weight neonates. J Pediatr 115:135-9

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