The aim of this research is to determine why the cell mediated immune response to HSV or CMV, following congenital or neonatal infections with these viruses, is impaired. The research is important because the infant survivors of neonatal HSV infections commonly have recurrent HSV skin lesions while those with congenital CMV excrete the virus in the urine for years. First line defense against herpesviruses is by antibody and NK cells: virus elimination requires T cells. Since affected infants make good antibody responses, this research will focus on NK and T cells.
Aim 1 documents the potential of normal newborns' NK cells to respond to HSV or CMV infected cells in cultures where T cell factors will be replaced by recombinant IL 2, IFN, or both. To allow for the likely heterogeneity of NK cells, three end-points will be at a single cell level (phenotype, target cell binding, cloning) and two at a population level (IFN production and virus plaque suppression).
Aim 2 will determine the susceptibility for lytic and non-lytic (latent) infections of normal newborn and adult MNC by laboratory strains and clinical isolates of HSV and CMV using a plaque assay and DNA hybridization. The extent to which normal NK, monocyte and T cell responses are interfered with by exposure to HSV or CMV will be measured using tests for NK cells, for antigen presentation and IL 1 production by monocytes and IL 2 production by T cells. The rationale for aims 1 and 2 is to characterize the potential interactions of HSV or CMV with newborns' MNC and the functional defects which may be induced.
Aim 3 is to characterize the defects of response which are present in the survivors of early infection. Neonatal HSV survivors' MNC will be tested for response to HSV by limiting dilution to enumerate proliferating T cells and by IL 2 production to detect antigen-responsive T cells, regardless of proliferation. NK activity will be measured by plaque suppression and antibody response by ELISA. Infants with congenital or neonatal CMV will be studied with the same range of tests except that the stimulating antigens and target cells will be CMV infected. Both groups of patients will be studied longitudinally to determine whether alterations in immune response accompany changes in the level of virus recurrence (for HSV) or excretion (for CMV). For subjects with congenital CMV correlations will be sought between the presence or absence of symptoms (hepatitis, throbmocytopenia, retardation) and their CMV-immune responsiveness.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD013733-07
Application #
3312277
Study Section
Experimental Virology Study Section (EVR)
Project Start
1980-09-29
Project End
1991-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
7
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Hayward, A R; Cosyns, M; Zhang, Y (1995) Frequency and cytokine phenotype of blood T cells from premature infants responding to staphylococcal enterotoxin B. Pediatr Res 37:455-9
Hayward, A; Cosyns, M (1994) Proliferative and cytokine responses by human newborn T cells stimulated with staphylococcal enterotoxin B. Pediatr Res 35:293-8
Hayward, A R; Zerbe, G O; Levin, M J (1994) Clinical application of responder cell frequency estimates with four years of follow up. J Immunol Methods 170:27-36
Hayward, A R; Read, G S; Cosyns, M (1993) Herpes simplex virus interferes with monocyte accessory cell function. J Immunol 150:190-6
Li, J; Campbell, D; Hayward, A R (1992) Differential response of human thymus cells to CD2 antibodies: fragmentation of DNA of CD45RO+ and proliferation of CD45RO- subsets. Immunology 75:305-10
Hayward, A; Shriber, M; Kubo, R et al. (1992) T-cell repopulation following neonatal injection of non-obese diabetic (NOD) mice with anti-T-cell antibodies. Immunology 76:110-6
Hayward, A R; Shriber, M (1992) Reduced incidence of insulitis in NOD mice following anti-CD3 injection: requirement for neonatal injection. J Autoimmun 5:59-67
Groothuis, J R; Levin, M J; Lehr, M V et al. (1992) Immune response to split-product influenza vaccine in preterm and full-term young children. Vaccine 10:221-5
Chinn, A; Cosyns, M; Hayward, A R (1990) T cell proliferative response to interleukin 2: different frequency of responders among CD45R0 and CD45RA subsets. Cell Immunol 131:132-9
Hayward, A R; Clarke, J; Cosyns, M (1990) V beta 5 and V beta 8 memory T cells in adults and infancy: co-ordinated increase in response to early antigen stimulus. Clin Exp Immunol 81:475-8

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