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.
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