Our studies are directed at understanding the mechanism by which Herpes-Simplex Virus-type 1 (HSV-1) infected targets are recognized and lysed by human natural killer (NK) cells. In these studies, both the heterogeneity of the effector cell population as well as sensitivity of the target cell itself to lysis will be considered. To investigate the heterogeneity at the effector cell level, studies will compare the effector cells which lyse HSV-infected fibroblasts to those which lyse HSV-1 infected lymphoblastoid cells and to the effectors which lyse K562 erythroleukemic cells. These effectors will be compared at the level of cell surface phenotype using monoclonal antibodies and in cold competition studies. To study the role of viral products and, in particular, viral glycoproteins in conferring susceptibility of infected cells to lysis, we will continue our investigations using viral mutants and biochemical inhibitors of various stages of virus replication. Virus mutants which fail to produce either alpha, beta, or gamma proteins will be studied to determine the effect of absence of these gene products on conferring susceptibility of targets to lysis. Metabolic inhibitors will include inhibitors of DNA synthesis as well as inhibitors of transcription and/or translation. These experiments will also include determinations of the susceptibility of the infected versus uninfected targets to cytotoxic factors including NK cytotoxic factor and rat cytotoxic granules. (LB)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042093-02
Application #
3182923
Study Section
Experimental Immunology Study Section (EI)
Project Start
1985-08-01
Project End
1987-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Medicine
DUNS #
605799469
City
Newark
State
NJ
Country
United States
Zip Code
07107
Howell, D M; Feldman, M; Siegal, F P et al. (1993) Peripheral blood of AIDS patients contains cells capable of providing accessory function for the natural killer cell-mediated, lysis of herpes simplex virus-infected targets despite low interferon-alpha production. J Acquir Immune Defic Syndr 6:15-23
Feldman, M; Howell, D; Fitzgerald-Bocarsly, P (1992) Interferon-alpha-dependent and -independent participation of accessory cells in natural killer cell-mediated lysis of HSV-1-infected fibroblasts. J Leukoc Biol 52:473-82
Fitzgerald-Bocarsly, P; Howell, D M; Pettera, L et al. (1991) Immediate-early gene expression is sufficient for induction of natural killer cell-mediated lysis of herpes simplex virus type 1-infected fibroblasts. J Virol 65:3151-60
Howell, D M; Fitzgerald-Bocarsly, P (1991) Natural killer-mediated lysis of some but not all HSV-1- or VSV-infected targets requires the participation of HLA-DR-positive accessory cells. Immunology 72:443-7
Feldman, M; Fitzgerald-Bocarsly, P (1990) Sequential enrichment and immunocytochemical visualization of human interferon-alpha-producing cells. J Interferon Res 10:435-46
Fitzgerald-Bocarsly, P; Feldman, M; Howell, D et al. (1989) Deficient interferon-alpha production but normal natural killer cell activity in an AIDS patient with HIV-2 infection. J Infect Dis 160:1084-5
Fitzgerald-Bocarsly, P; Feldman, M; Curl, S et al. (1989) Positively selected Leu-11a (CD16+) cells require the presence of accessory cells or factors for the lysis of herpes simplex virus-infected fibroblasts but not herpes simplex virus-infected Raji. J Immunol 143:1318-26
Fitzgerald-Bocarsly, P; Feldman, M; Mendelsohn, M et al. (1988) Human mononuclear cells which produce interferon-alpha during NK(HSV-FS) assays are HLA-DR positive cells distinct from cytolytic natural killer effectors. J Leukoc Biol 43:323-34
Amos, L J; Duggal, A; Mirsky, E J et al. (1988) Morphological variation at the [NiFe(CN)6]2--derivatized nickel electrode: a technique for the evaluation of alkali cation containing solutions. Anal Chem 60:245-9