Mechanism of Recognition of Herpes Simplex Virus Type 1-infected Cells by Natural Killer Cells

Abstract

SUMMARYHuman fibroblast FS-4 cells when infected with herpes simplex virus type 1 (HSV-1) become susceptible to lysis by purified populations of T3-human natural killer (NK) lymphocytes. Blocking of HSV-1 protein synthesis or N-linked glycosylation with pactamycin or tunicamycin, respectively, prevented HSV-l-infected cells from being lysed, suggesting that HSV-1 glycoprotein synthesis is required for recognition by NK cells. However, pactamycin-and tunicamycin-treated cells expressed on their membranes a detectable amount (20 to 40% of the untreated control) of HSV-1 glycoproteins gB, gC and gD, left by the virus during its internalization. Phosphonoformic acid (PFA) blocked HSV-1 DNA replication and inhibited the synthesis and surface expression of newly made gC, gD and gB by 90, 80 and 60% respectively. Despite this reduction, PFA treatment had no effect on NK susceptibility. The target structure recognized seems to be different from those expressed on tumour target cells since there was no competition for the lysis of HSV-1-infected FS-4 by K-562 or HeLa tumour target cells. However, a monoclonal antibody specific for the human transferrin receptor which inhibited NK recognition of tumour cells also blocked NK cytotoxicity of HSV-l-infected cells. In summary our results indicate that although viral glycoprotein synthesis is required, gB, gC and/or gD alone are not the targets for NK recognition of HSV-1-infected cells. In addition, they suggest the involvement of the host cell transferrin receptor in the NK killing process.

Expression of ICP0 Is Sufficient to Trigger Natural Killer Cell Recognition of Herpes Simplex Virus–Infected Cells by Natural Cytotoxicity Receptors

“…Thus, these data suggest that 2 distinct mechanisms trigger the induction of ligands for the NCR and target cell susceptibility to NK lysis on infection with HSV-1: one dependent on ICP0 and a second that depends on the action of some viral gene expressed during lytic infection. The identity of this other viral protein is as yet unknown, but the present model might help resolve earlier controversies about the relative importance of IE proteins or viral glycoproteins as target antigens recognized by NK cells on HSV-infected targets [28,48,49].…”

Immediate-early gene expression is sufficient for induction of natural killer cell-mediated lysis of herpes simplex virus type 1-infected fibroblasts

“…Role of HSV-1 immediate-early gene expression in conferring target susceptibility to lysis. Convincing evidence for a role for early viral gene expression in conferring susceptibility of virus-infected targets to lysis by both NK and cytotoxic T cells has been developed recently (8,12,31). To evaluate the role of immediate-early gene expression in HSV-1-infected targets, we used tsLB2, a temperaturesensitive HSV mutant which at the nonpermissive tempera- 4.…”

“…Bishop et al (3,5,6) reported that HSV glycoproteins are the relevant structures recognized on infected fibroblast or WISH epithelial cell targets. However, Borysiewicz et al (7) and Lopez-Guerrero et al (31) have failed to demonstrate a role for viral glycoproteins in the lysis of cytomegalovirus (CMV)or HSV-infected targets, respectively, and have instead implicated a role for early viral genes or a cellular gene product. Similarly, in a bovine herpesvirus (BHV) system, Cook and Splitter (11) have suggested that viral glycoproteins are not essential for the lysis of targets infected with BHV.…”

The Fc Domain of Immunoglobulin Is Sufficient to Bridge NK Cells with Virally Infected Cells

“…While HSV1 infection in a heathy population is usually self-limited and shows no or very mild symptoms (Gilden et al, 2007), patients with NK cell deficiencies can suffer severe, recurrent, and sometimes fatal HSV1 infection (Biron et al, 1989), suggesting a critical role for NK cells in control of HSV1 infection. The HSV1 genome contains 84 open reading frames, encoding 74 unique viral proteins (Szpara et al, 2010); only few genes have been studied for their roles in modulating the function of NK cells with some controversial results (Bishop et al, 1983; Chisholm et al, 2007; Fitzgerald-Bocarsly et al, 1991; Huard and Fruh, 2000; Imai et al, 2013; Lopez-Guerrero et al, 1988). How NK cells mechanistically recognize and clear primary HSV1 infection (i.e., before antigen specific immunity is generated) is unclear.…”