Replication of human cytomegalovirus in cells deficient in beta2-microglobulin gene expression

Abstract

To study the roles offl2-microglobulin (fl~-m) and major histocompatibility complex (MHC) class I expression in human cytomegalovirus (HCMV) infection, the ability of HCMV strain AD-169 to infect and replicate in a human melanoma cell line (FO-1), which is fl2-mdeficient and cannot express MHC class I on its cell surface, was examined. Susceptibility of FO-1 cells was compared with human foreskin fibroblasts (HFF) and FO-1H cells (FO-1 cells that have been transfected with the human fl2-m gene, restoring MHC I expression on the cell surface). As judged by the HCMV immediate early 1 (IE-1) antigen expression, HCMV was able to infect FO-1 cells, although somewhat less efficiently than HFF. However, the expression of HCMV late (L) antigen and the production of virus was significantly less for FO-1 cells than for HFF. Analysis of the FO-1H transfectants revealed that expression of IE-1 and L HCMV antigens was comparable to FO-1 cells, which lack MHC I. Treatment of FO-1 and FO-1H cells with sodium butyrate prior to inoculation did not alter the expression ofMHC I in either cell type, but did increase susceptibility of both cell types to HCMV infection, as well as the expression of L antigens and production of virus. These studies indicate that HCMV infection of FO-1 cells is independent of fl2-m and MHC class I expression.Human cytomegalovirus (HCMV) is a herpesvirus that causes significant diseases in immunocompromised individuals and in congenitally infected newborns (Weller, 1971;Adler, 1990;Betts & Hanshaw, 1977). To understand the interactions of a virus with a host, it is crucial to characterize the early interactions with target cells. A number of receptors have been identified for human pathogenic viruses, including CR2 for Epstein-Barr virus (Fingeroth et al., 1984;Nemerow et al., 1985), CD4 for human immunodeficiency virus (Dalgleish et al., 1984) and ICAM-1 for rhinoviruses (Staunton et al., 1989). Although our understanding of HCMV infection of cells has significantly increased, the mechanisms involved in initiating HCMV infection remain difficult to characterize. A number of candidates have been considered as the cellular receptors that mediate HCMV infection (Taylor & Cooper, 1989;Cooper et al., 1991 ;Nowlin et al., 1991 ;Compton et al., 1992Compton et al., , 1993Keay et al., 1989).Previous reports that HCMV avidly associates with fl2-microglobulin (fl2-m) led to the hypothesis that HCMV may use the major histocompatibility complex (MHC) class I complex as one route to initiate infection (Grundy, 1990). The MHC I molecules are glycosylated transmembrane polypeptides, which are non-covalently associated with the non-glycosylated protein, fl~-m, fl2-m association is necessary for the processing, transport and expression of the MHC I antigens on the cell surface (Cox et al., 1990;Sege et al., 1981). To examine the role of fl2-m and MHC I in HCMV infection, the FO-1 cell line, which is unable to express MHC I molecules on the cell surface owing to a deletion mutation of the fl2-m gene (D'urso et al., 1990)...

Virus-Specific CD8+ T Cells Infiltrate Melanoma Lesions and Retain Function Independently of PD-1 Expression

“…CMV protein has been found in multiple human tumors [28–31], can infect leukemia and melanoma in vitro [24, 32, 33] and we have seen MCMV DNA in B16F0 tumors from acutely and latently infected animals (data not shown). Thus, it is possible that MCMV-specific T cells entered tumors because the tumors were infected.…”

β2-Microglobulin deficiency causes a complex immunodeficiency of the innate and adaptive immune system

“…6 Despite these abnormalities in NK and CD8 T-cell activation, MHC-I deficiency is not associated with an overt susceptibility toward viral infection in patients or mice. [27][28][29][30][31][32][33] Additional protective mechanisms include the induction and recruitment of cytotoxic CD4 T cells 33,34 and other effector mechanisms that do not depend on b 2 m. [35][36][37][38] In addition to immunologic similarities between b 2 m deficiency and TAP deficiency, there are several clear-cut differences. Through the formation of heterodimers, b 2 m not only stabilizes surface expression of MHC-I but also of the other members of the MHC-I family: FcRn, CD1a, HLA-G, HLA-E, and hemochromatosis protein.…”

β-Conglycinin Regulates Intestinal Immunity through the CIITA-mediated MHC II-PI3K/Akt/mTOR Pathway in Hybrid Grouper: The Ameliorative Effects of Sodium Butyrate (NaB)

“…These observation thus tend to indicate that dietary supplementation with NaB has the effect of enhancing the e ciency of antigenic protein presentation and processing in hybrid groupers. In addition, a concomitant reduction in the expression of MHC I may be indicative of a reduction in the severity of the in ammatory response compared with that seen in groupers receiving a high dose of 7S in the absence of NaB 58 . In addition GILT and AEP are inhibited during the development of nucleosomes, which subsequently migrate to the lysosomes and Golgi apparatus.…”