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. 1997 Jun;71(6):4657–4662. doi: 10.1128/jvi.71.6.4657-4662.1997

Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes.

Q Li 1, M K Spriggs 1, S Kovats 1, S M Turk 1, M R Comeau 1, B Nepom 1, L M Hutt-Fletcher 1
PMCID: PMC191687  PMID: 9151859

Abstract

Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. Interference with this interaction with a soluble form of gp42, with a monoclonal antibody (MAb) to gp42, or with a MAb to HLA-DR inhibited virus infection. It was not possible to superinfect cells that failed to express HLA-DR unless expression was restored by transfection or creation of hybrid cell lines with complementing deficiencies in expression of HLA class II. HLA class II molecules thus serve as cofactors for infection of human B cells.

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Selected References

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  1. Ahearn J. M., Hayward S. D., Hickey J. C., Fearon D. T. Epstein-Barr virus (EBV) infection of murine L cells expressing recombinant human EBV/C3d receptor. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9307–9311. doi: 10.1073/pnas.85.23.9307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alkhatib G., Combadiere C., Broder C. C., Feng Y., Kennedy P. E., Murphy P. M., Berger E. A. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1. Science. 1996 Jun 28;272(5270):1955–1958. doi: 10.1126/science.272.5270.1955. [DOI] [PubMed] [Google Scholar]
  3. Baer R., Bankier A. T., Biggin M. D., Deininger P. L., Farrell P. J., Gibson T. J., Hatfull G., Hudson G. S., Satchwell S. C., Séguin C. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature. 1984 Jul 19;310(5974):207–211. doi: 10.1038/310207a0. [DOI] [PubMed] [Google Scholar]
  4. Bull M., van Hoef A., Gorski J. Transcription analysis of class II human leukocyte antigen genes from normal and immunodeficient B lymphocytes, using polymerase chain reaction. Mol Cell Biol. 1990 Jul;10(7):3792–3796. doi: 10.1128/mcb.10.7.3792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Carel J. C., Frazier B., Ley T. J., Holers V. M. Analysis of epitope expression and the functional repertoire of recombinant complement receptor 2 (CR2/CD21) in mouse and human cells. J Immunol. 1989 Aug 1;143(3):923–930. [PubMed] [Google Scholar]
  6. DeMars R., Chang C. C., Shaw S., Reitnauer P. J., Sondel P. M. Homozygous deletions that simultaneously eliminate expressions of class I and class II antigens of EBV-transformed B-lymphoblastoid cells. I. Reduced proliferative responses of autologous and allogeneic T cells to mutant cells that have decreased expression of class II antigens. Hum Immunol. 1984 Oct;11(2):77–97. doi: 10.1016/0198-8859(84)90047-8. [DOI] [PubMed] [Google Scholar]
  7. Deng H., Liu R., Ellmeier W., Choe S., Unutmaz D., Burkhart M., Di Marzio P., Marmon S., Sutton R. E., Hill C. M. Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996 Jun 20;381(6584):661–666. doi: 10.1038/381661a0. [DOI] [PubMed] [Google Scholar]
  8. Doranz B. J., Rucker J., Yi Y., Smyth R. J., Samson M., Peiper S. C., Parmentier M., Collman R. G., Doms R. W. A dual-tropic primary HIV-1 isolate that uses fusin and the beta-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell. 1996 Jun 28;85(7):1149–1158. doi: 10.1016/s0092-8674(00)81314-8. [DOI] [PubMed] [Google Scholar]
  9. Dragic T., Litwin V., Allaway G. P., Martin S. R., Huang Y., Nagashima K. A., Cayanan C., Maddon P. J., Koup R. A., Moore J. P. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996 Jun 20;381(6584):667–673. doi: 10.1038/381667a0. [DOI] [PubMed] [Google Scholar]
  10. Durand B., Kobr M., Reith W., Mach B. Functional complementation of major histocompatibility complex class II regulatory mutants by the purified X-box-binding protein RFX. Mol Cell Biol. 1994 Oct;14(10):6839–6847. doi: 10.1128/mcb.14.10.6839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fanslow W. C., Anderson D. M., Grabstein K. H., Clark E. A., Cosman D., Armitage R. J. Soluble forms of CD40 inhibit biologic responses of human B cells. J Immunol. 1992 Jul 15;149(2):655–660. [PubMed] [Google Scholar]
  12. Feng Y., Broder C. C., Kennedy P. E., Berger E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996 May 10;272(5263):872–877. doi: 10.1126/science.272.5263.872. [DOI] [PubMed] [Google Scholar]
  13. Fingeroth J. D., Weis J. J., Tedder T. F., Strominger J. L., Biro P. A., Fearon D. T. Epstein-Barr virus receptor of human B lymphocytes is the C3d receptor CR2. Proc Natl Acad Sci U S A. 1984 Jul;81(14):4510–4514. doi: 10.1073/pnas.81.14.4510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Forghani B., Ni L., Grose C. Neutralization epitope of the varicella-zoster virus gH:gL glycoprotein complex. Virology. 1994 Mar;199(2):458–462. doi: 10.1006/viro.1994.1145. [DOI] [PubMed] [Google Scholar]
  15. Forrester A., Farrell H., Wilkinson G., Kaye J., Davis-Poynter N., Minson T. Construction and properties of a mutant of herpes simplex virus type 1 with glycoprotein H coding sequences deleted. J Virol. 1992 Jan;66(1):341–348. doi: 10.1128/jvi.66.1.341-348.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fuller A. O., Santos R. E., Spear P. G. Neutralizing antibodies specific for glycoprotein H of herpes simplex virus permit viral attachment to cells but prevent penetration. J Virol. 1989 Aug;63(8):3435–3443. doi: 10.1128/jvi.63.8.3435-3443.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Furnari F. B., Zacny V., Quinlivan E. B., Kenney S., Pagano J. S. RAZ, an Epstein-Barr virus transdominant repressor that modulates the viral reactivation mechanism. J Virol. 1994 Mar;68(3):1827–1836. doi: 10.1128/jvi.68.3.1827-1836.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gayle M. A., Sims J. E., Dower S. K., Slack J. L. Monoclonal antibody 1994-01 (also known as ALVA 42) reported to recognize type II IL-1 receptor is specific for HLA-DR alpha and beta chains. Cytokine. 1994 Jan;6(1):83–86. doi: 10.1016/1043-4666(94)90012-4. [DOI] [PubMed] [Google Scholar]
  19. Gompels U., Minson A. The properties and sequence of glycoprotein H of herpes simplex virus type 1. Virology. 1986 Sep;153(2):230–247. doi: 10.1016/0042-6822(86)90026-7. [DOI] [PubMed] [Google Scholar]
  20. Haddad R. S., Hutt-Fletcher L. M. Depletion of glycoprotein gp85 from virosomes made with Epstein-Barr virus proteins abolishes their ability to fuse with virus receptor-bearing cells. J Virol. 1989 Dec;63(12):4998–5005. doi: 10.1128/jvi.63.12.4998-5005.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Henle W., Henle G., Zajac B. A., Pearson G., Waubke R., Scriba M. Differential reactivity of human serums with early antigens induced by Epstein-Barr virus. Science. 1970 Jul 10;169(3941):188–190. doi: 10.1126/science.169.3941.188. [DOI] [PubMed] [Google Scholar]
  22. Heston L., Rabson M., Brown N., Miller G. New Epstein-Barr virus variants from cellular subclones of P3J-HR-1 Burkitt lymphoma. Nature. 1982 Jan 14;295(5845):160–163. doi: 10.1038/295160a0. [DOI] [PubMed] [Google Scholar]
  23. Hoffman G. J., Lazarowitz S. G., Hayward S. D. Monoclonal antibody against a 250,000-dalton glycoprotein of Epstein-Barr virus identifies a membrane antigen and a neutralizing antigen. Proc Natl Acad Sci U S A. 1980 May;77(5):2979–2983. doi: 10.1073/pnas.77.5.2979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hume C. R., Shookster L. A., Collins N., O'Reilly R., Lee J. S. Bare lymphocyte syndrome: altered HLA class II expression in B cell lines derived from two patients. Hum Immunol. 1989 May;25(1):1–11. doi: 10.1016/0198-8859(89)90065-7. [DOI] [PubMed] [Google Scholar]
  25. Hutchinson L., Browne H., Wargent V., Davis-Poynter N., Primorac S., Goldsmith K., Minson A. C., Johnson D. C. A novel herpes simplex virus glycoprotein, gL, forms a complex with glycoprotein H (gH) and affects normal folding and surface expression of gH. J Virol. 1992 Apr;66(4):2240–2250. doi: 10.1128/jvi.66.4.2240-2250.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kaye J. F., Gompels U. A., Minson A. C. Glycoprotein H of human cytomegalovirus (HCMV) forms a stable complex with the HCMV UL115 gene product. J Gen Virol. 1992 Oct;73(Pt 10):2693–2698. doi: 10.1099/0022-1317-73-10-2693. [DOI] [PubMed] [Google Scholar]
  27. Knox P. G., Young L. S. Epstein-Barr virus infection of CR2-transfected epithelial cells reveals the presence of MHC class II on the virion. Virology. 1995 Oct 20;213(1):147–157. doi: 10.1006/viro.1995.1555. [DOI] [PubMed] [Google Scholar]
  28. Kovats S., Nepom G. T., Coleman M., Nepom B., Kwok W. W., Blum J. S. Deficient antigen-presenting cell function in multiple genetic complementation groups of type II bare lymphocyte syndrome. J Clin Invest. 1995 Jul;96(1):217–223. doi: 10.1172/JCI118023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kwok W. W., Schwarz D., Nepom B. S., Hock R. A., Thurtle P. S., Nepom G. T. HLA-DQ molecules form alpha-beta heterodimers of mixed allotype. J Immunol. 1988 Nov 1;141(9):3123–3127. [PubMed] [Google Scholar]
  30. Lampson L. A., Levy R. Two populations of Ia-like molecules on a human B cell line. J Immunol. 1980 Jul;125(1):293–299. [PubMed] [Google Scholar]
  31. Li Q., Turk S. M., Hutt-Fletcher L. M. The Epstein-Barr virus (EBV) BZLF2 gene product associates with the gH and gL homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells. J Virol. 1995 Jul;69(7):3987–3994. doi: 10.1128/jvi.69.7.3987-3994.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lisowska-Grospierre B., Charron D. J., de Préval C., Durandy A., Griscelli C., Mach B. A defect in the regulation of major histocompatibility complex class II gene expression in human HLA-DR negative lymphocytes from patients with combined immunodeficiency syndrome. J Clin Invest. 1985 Jul;76(1):381–385. doi: 10.1172/JCI111974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Liu D. X., Gompels U. A., Nicholas J., Lelliott C. Identification and expression of the human herpesvirus 6 glycoprotein H and interaction with an accessory 40K glycoprotein. J Gen Virol. 1993 Sep;74(Pt 9):1847–1857. doi: 10.1099/0022-1317-74-9-1847. [DOI] [PubMed] [Google Scholar]
  34. Martin D. R., Marlowe R. L., Ahearn J. M. Determination of the role for CD21 during Epstein-Barr virus infection of B-lymphoblastoid cells. J Virol. 1994 Aug;68(8):4716–4726. doi: 10.1128/jvi.68.8.4716-4726.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Menezes J., Seigneurin J. M., Patel P., Bourkas A., Lenoir G. Presence of Epstein-Barr virus receptors, but absence of virus penetration, in cells of an Epstein-Barr virus genome-negative human lymphoblastoid T line (Molt 4). J Virol. 1977 Jun;22(3):816–821. doi: 10.1128/jvi.22.3.816-821.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Miller N., Hutt-Fletcher L. M. A monoclonal antibody to glycoprotein gp85 inhibits fusion but not attachment of Epstein-Barr virus. J Virol. 1988 Jul;62(7):2366–2372. doi: 10.1128/jvi.62.7.2366-2372.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Miller N., Hutt-Fletcher L. M. Epstein-Barr virus enters B cells and epithelial cells by different routes. J Virol. 1992 Jun;66(6):3409–3414. doi: 10.1128/jvi.66.6.3409-3414.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Montgomery R. I., Warner M. S., Lum B. J., Spear P. G. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell. 1996 Nov 1;87(3):427–436. doi: 10.1016/s0092-8674(00)81363-x. [DOI] [PubMed] [Google Scholar]
  39. Nemerow G. R., Cooper N. R. Early events in the infection of human B lymphocytes by Epstein-Barr virus: the internalization process. Virology. 1984 Jan 15;132(1):186–198. doi: 10.1016/0042-6822(84)90102-8. [DOI] [PubMed] [Google Scholar]
  40. Nemerow G. R., Mold C., Schwend V. K., Tollefson V., Cooper N. R. Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d. J Virol. 1987 May;61(5):1416–1420. doi: 10.1128/jvi.61.5.1416-1420.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. PULVERTAFT J. V. CYTOLOGY OF BURKITT'S TUMOUR (AFRICAN LYMPHOMA). Lancet. 1964 Feb 1;1(7327):238–240. doi: 10.1016/s0140-6736(64)92345-1. [DOI] [PubMed] [Google Scholar]
  42. Pearson G. R., Vroman B., Chase B., Sculley T., Hummel M., Kieff E. Identification of polypeptide components of the Epstein-Barr virus early antigen complex with monoclonal antibodies. J Virol. 1983 Jul;47(1):193–201. doi: 10.1128/jvi.47.1.193-201.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Reisert P. S., Spiro R. C., Townsend P. L., Stanford S. A., Sairenji T., Humphreys R. E. Functional association of class II antigens with cell surface binding of Epstein-Barr virus. J Immunol. 1985 Jun;134(6):3776–3780. [PubMed] [Google Scholar]
  44. Roeckel D., Mueller-Lantzsch N. Biochemical characterization of two Epstein-Barr virus early antigen-associated phosphopolypeptides. Virology. 1985 Dec;147(2):253–263. doi: 10.1016/0042-6822(85)90128-x. [DOI] [PubMed] [Google Scholar]
  45. Roop C., Hutchinson L., Johnson D. C. A mutant herpes simplex virus type 1 unable to express glycoprotein L cannot enter cells, and its particles lack glycoprotein H. J Virol. 1993 Apr;67(4):2285–2297. doi: 10.1128/jvi.67.4.2285-2297.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Scholl P. R., Geha R. S. MHC class II signaling in B-cell activation. Immunol Today. 1994 Sep;15(9):418–422. doi: 10.1016/0167-5699(94)90271-2. [DOI] [PubMed] [Google Scholar]
  47. Seidl C., Saraiya C., Osterweil Z., Fu Y. P., Lee J. S. Genetic complexity of regulatory mutants defective for HLA class II gene expression. J Immunol. 1992 Mar 1;148(5):1576–1584. [PubMed] [Google Scholar]
  48. Spaete R. R., Perot K., Scott P. I., Nelson J. A., Stinski M. F., Pachl C. Coexpression of truncated human cytomegalovirus gH with the UL115 gene product or the truncated human fibroblast growth factor receptor results in transport of gH to the cell surface. Virology. 1993 Apr;193(2):853–861. doi: 10.1006/viro.1993.1194. [DOI] [PubMed] [Google Scholar]
  49. Spriggs M. K., Armitage R. J., Comeau M. R., Strockbine L., Farrah T., Macduff B., Ulrich D., Alderson M. R., Müllberg J., Cohen J. I. The extracellular domain of the Epstein-Barr virus BZLF2 protein binds the HLA-DR beta chain and inhibits antigen presentation. J Virol. 1996 Aug;70(8):5557–5563. doi: 10.1128/jvi.70.8.5557-5563.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Steimle V., Otten L. A., Zufferey M., Mach B. Complementation cloning of an MHC class II transactivator mutated in hereditary MHC class II deficiency (or bare lymphocyte syndrome). Cell. 1993 Oct 8;75(1):135–146. [PubMed] [Google Scholar]
  51. Takada K. Cross-linking of cell surface immunoglobulins induces Epstein-Barr virus in Burkitt lymphoma lines. Int J Cancer. 1984 Jan 15;33(1):27–32. doi: 10.1002/ijc.2910330106. [DOI] [PubMed] [Google Scholar]
  52. Tanner J., Weis J., Fearon D., Whang Y., Kieff E. Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell. 1987 Jul 17;50(2):203–213. doi: 10.1016/0092-8674(87)90216-9. [DOI] [PubMed] [Google Scholar]
  53. Trkola A., Dragic T., Arthos J., Binley J. M., Olson W. C., Allaway G. P., Cheng-Mayer C., Robinson J., Maddon P. J., Moore J. P. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5. Nature. 1996 Nov 14;384(6605):184–187. doi: 10.1038/384184a0. [DOI] [PubMed] [Google Scholar]
  54. Van Voorhis W. C., Steinman R. M., Hair L. S., Luban J., Witmer M. D., Koide S., Cohn Z. A. Specific antimononuclear phagocyte monoclonal antibodies. Application to the purification of dendritic cells and the tissue localization of macrophages. J Exp Med. 1983 Jul 1;158(1):126–145. doi: 10.1084/jem.158.1.126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Wickham T. J., Mathias P., Cheresh D. A., Nemerow G. R. Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell. 1993 Apr 23;73(2):309–319. doi: 10.1016/0092-8674(93)90231-e. [DOI] [PubMed] [Google Scholar]
  56. Wu L., Gerard N. P., Wyatt R., Choe H., Parolin C., Ruffing N., Borsetti A., Cardoso A. A., Desjardin E., Newman W. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996 Nov 14;384(6605):179–183. doi: 10.1038/384179a0. [DOI] [PubMed] [Google Scholar]
  57. Yao Z., Fanslow W. C., Seldin M. F., Rousseau A. M., Painter S. L., Comeau M. R., Cohen J. I., Spriggs M. K. Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity. 1995 Dec;3(6):811–821. doi: 10.1016/1074-7613(95)90070-5. [DOI] [PubMed] [Google Scholar]
  58. Yaswen L. R., Stephens E. B., Davenport L. C., Hutt-Fletcher L. M. Epstein-Barr virus glycoprotein gp85 associates with the BKRF2 gene product and is incompletely processed as a recombinant protein. Virology. 1993 Aug;195(2):387–396. doi: 10.1006/viro.1993.1388. [DOI] [PubMed] [Google Scholar]
  59. Zhou H., Glimcher L. H. Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency. Immunity. 1995 May;2(5):545–553. doi: 10.1016/1074-7613(95)90034-9. [DOI] [PubMed] [Google Scholar]
  60. de Préval C., Lisowska-Grospierre B., Loche M., Griscelli C., Mach B. A trans-acting class II regulatory gene unlinked to the MHC controls expression of HLA class II genes. Nature. 1985 Nov 21;318(6043):291–293. doi: 10.1038/318291a0. [DOI] [PubMed] [Google Scholar]

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