Research Project
3135138
Herpes viruses, including herpes simplex viruses (HSV), Epstein-Barr virus (EBV), herpes varicella-zoster (HVZ) and cytomegalovirus (CMV) may cause cancer and/or induce latent or recurrent infections that can be fatal in immunosuppressed cancer patients and recipients of kidney and bone marrow transplants. Much evidence suggests that natural killer (NK) and T cell mediated immunity play roles in resistance to HSV but little is known concerning human NK cells' ability to lyse autologous cells infected with autologous HSV isolates, the functional types of human T cells responsive to herpews viruses and which herpes glycoproteins are recognized by human T cells. The ability now to distinguish human cytotoxic T cells (CTL) from NK cells and to generate HSV-specific T cell clones, enables the following aims to be addressed: (1) to compare lytic activity of PBL from normal individuals and patients with recurrent HSV infections against autologous HSV-infected cells, to determine if lysis is mediated by NK cells and/or CTL and to determine if interleukin-2 or non-toxic analogs of poly I:C augments cytotoxicity against autologous HSV infected cells; (2) to generate HSV-specific T cell clones from healthy HSV seropositive donors and elucidate their functions, i.e. helper (Th), cytotoxic (CTL), and/or bifunctional with both activities (HITc); (3) to determine which viral glycoproteins are recognized by HSV specific T cell clones, by using target cells infected with HSV-1 x HSV-2 intertypic recombinants and HSV mutants; monoclonal antibodies to HSV glycoproteins, and purified HSV glycoproteins; (4) to compare the frequencies of CTL and Th precursors, by limiting dilution assays, from PBL of healthy HSV seropositive individuals with those from PBL of patients with recurrent HSV infections, to compare the proportions of T cell clones that are CTL, Th and HITc in these groups of individuals, and determine whether the same HSV glycoproteins are recognized by clones from normals and patients; and (5) to elucidate functional types of HSV specific T cell clones and their fine specificity generated from PBL of individuals immunized with a non-infectious HSV-2 glycoprotein subunit vaccine. Results of these studies are expected to provide information concerning the function and fine specificity of cell mediated immune responses to HSV in man, and may provide insight into the immunological basis for recurrence. Ultimately, such studies may contribute to the development of new forms of immunotherapy and HSV subunit vaccines.
