Alternate replication in b cells and epithelial cells switches tropism of epstein–barr virus

ABSTRACT Epstein–Barr virus is ubiquitous and is causally implicated in lymphoid and epithelial malignancies. Virus invades oropharyngeal mucosa and establishes latency in B lymphocytes.

Reactivating lymphocytes shed virus into saliva for spread to new hosts. A complex of three virus glycoproteins, gH, gL and gp42, is essential for entry. B-cell entry requires binding of

gp42 to human leukocyte antigen (HLA) class II whereas entry into epithelial cells lacking HLA class II requires complexes without gp42. To accommodate infection of each, the virus carries

both three-part and two-part complexes. We show here that HLA class II in the virus-producing cell alters the ratio of three-part to two-part complexes. As a consequence, virus originating

in epithelial cells efficiently infects B cells whereas B-cell–derived virus better infects epithelial cells. This molecular switch is a novel strategy that could alter tropism of virus from

epithelium to B cells and then back to epithelium in a new host. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution

ACCESS OPTIONS Access through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article *

Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn

about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS TRANSCRIPTOME REPROGRAMMING OF EPSTEIN-BARR VIRUS INFECTED EPITHELIAL AND

B CELLS REVEALS DISTINCT HOST-VIRUS INTERACTION PROFILES Article Open access 22 October 2022 A POTENT AND PROTECTIVE HUMAN NEUTRALIZING ANTIBODY TARGETING A NOVEL VULNERABLE SITE OF

EPSTEIN-BARR VIRUS Article Open access 16 November 2021 INTERFERON-INDUCED TRANSMEMBRANE PROTEIN-1 COMPETITIVELY BLOCKS EPHRIN RECEPTOR A2-MEDIATED EPSTEIN–BARR VIRUS ENTRY INTO EPITHELIAL

CELLS Article Open access 22 April 2024 REFERENCES * Rickinson, A.B. & Kieff, E. Epstein–Barr Virus. in _Fields Virology_, Vol. 2 (eds. Knipe, D.M. & Howley, P.M.) 2575–2627

(Lippincott Williams and Wilkins, Philadelphia, 2001). Google Scholar  * Spear, P.G., Eisenberg, R.J. & Cohen, G.H. Three classes of cell surface receptors for alphaherpesvirus entry.

_Virology_ 275, 1–8 (2000). Article  CAS  Google Scholar  * 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._ 61, 1416–1420 (1987). CAS  PubMed

  Google Scholar  * 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_ 50, 203–213 (1987). Article  CAS  Google Scholar  * Fingeroth, J.D. et al. Epstein–Barr virus receptor of human B lymphocytes is the C3d complement CR2. _Proc. Natl.

Acad. Sci. USA_ 81, 4510–4516 (1984). Article  CAS  Google Scholar  * Nemerow, G.R., Wolfert, R., McNaughton, M. & Cooper, N.R. Identification and characterization of the Epstein–Barr

virus receptor on human B lymphocytes and its relationship to the C3d complement receptor (CR2). _J. Virol._ 55, 347–351 (1985). CAS  PubMed  Google Scholar  * Molesworth, S.J., Lake, C.M.,

Borza, C.M., Turk, S.M. & Hutt-Fletcher, L.M. Epstein–Barr virus gH is essential for penetration of B cell but also plays a role in attachment of virus to epithelial cells. _J. Virol._

74, 6324–6332 (2000). Article  CAS  Google Scholar  * Miller, N. & Hutt-Fletcher, L.M. A monoclonal antibody to glycoprotein gp85 inhibits fusion but not attachment of Epstein–Barr

virus. _J. Virol._ 62, 2366–2372 (1988). CAS  PubMed  Google Scholar  * 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._ 63, 4998–5005 (1989). CAS  PubMed  Google Scholar  * Li, Q.X., Turk, S.M. & Hutt-Fletcher, L.M.

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._ 69,

3987–3994 (1995). CAS  PubMed  Google Scholar  * Wang, X. & Hutt-Fletcher, L.M. Epstein–Barr virus lacking glycoprotein gp42 can bind to B cells but is not able to infect. _J. Virol._

72, 158–163 (1998). CAS  PubMed  Google Scholar  * Li, Q.X. et al. Epstein–Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. _J. Virol._ 71, 4657–4662 (1997). CAS 

PubMed  Google Scholar  * Haan, K.M., Kwok, W.W., Longnecker, R. & Speck, P. Epstein–Barr virus entry utilizing HLA-DP or HLA-DQ as a coreceptor. _J. Virol._ 74, 2451–2454 (2000).

Article  CAS  Google Scholar  * Haan, K.M. & Longnecker, R. Coreceptor restriction within the HLA-DQ locus for Epstein–Barr virus infection. _Proc. Natl. Acad. Sci. USA_ 97, 9252–9257

(2000). Article  CAS  Google Scholar  * Wang, X., Kenyon, W.J., Li, Q.X., Mullberg, J. & Hutt-Fletcher, L.M. Epstein–Barr virus uses different complexes of glycoproteins gH and gL to

infect B lymphocytes and epithelial cells. _J. Virol._ 72, 5552–5558 (1998). CAS  PubMed  Google Scholar  * Borza, C.M. & Hutt-Fletcher, L.M. Epstein–Barr virus recombinant lacking

expression of glycoprotein gp150 infects B cells normally but is enhanced for infection of the epithelial line SVKCR2. _J. Virol._ 72, 7577–7582 (1998). CAS  PubMed  Google Scholar  *

Mellman, I., Pierre, P. & Amigorena, S. Lonely MHC molecules seeking immunogenic peptides for meaningful relationships. _Curr. Opin. Cell Biol._ 7, 564–572 (1995). Article  CAS  Google

Scholar  * Chang, C.H., Fontes, J.D., Peterlin, M. & Flavell, R.A. Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatability complex class II

genes. _J. Exp. Med._ 180, 1367–1374 (1994). Article  CAS  Google Scholar  * Goff, S.P. _Retroviridae_: The retroviruses and their replication. in _Fields Virology_, Vol II (eds. Knipe,

D.M. & Howley, P.M.) 1871–1939 (Lippincott Williams and Wilkins, Philadelphia, 2001). Google Scholar  * Geraghty, R.J., Jogger, C.R. & Spear, P.G. Cellular expression of

alphaherpesvirus gD interferes with entry of homologous and heterologous alphaherpesviruses by blocking access to a shared gD receptor. _Virology_ 268, 147–158 (2000). Article  CAS  Google

Scholar  * Li, Q.X. et al. Epstein–Barr virus infection and replication in a human epithelial system. _Nature_ 356, 347–350 (1992). Article  CAS  Google Scholar  * Svedmyr, E. et al.

Virologic, immunologic, and clinical observations on a patient during the incubation, acute and convalescent phases of infectious mononucleosis. _Clin. Immunol. Pathol._ 30, 437–450 (1984).

CAS  Google Scholar  * Callan, M.F. et al. Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein–Barr virus _in vivo_. _J. Exp. Med._ 187,

1395–1402 (1998). Article  CAS  Google Scholar  * Moghaddam, A. et al. An animal model for acute and persistent Epstein–Barr virus infection. _Science_ 276, 2030–2033 (1997). Article  CAS 

Google Scholar  * Van Vooris, W.C. et al. Specific anti-mononuclear antibodies. Application to the purification of dendritic cells and the tissue localization of macrophages. _J. Exp. Med._

158, 126–145 (1983). Article  Google Scholar  * Takada, K. Cross-linking of cell surface immunoglobulin induces Epstein–Barr virus in Burkitt lymphoma lines. _Int. J. Cancer_ 33, 27–32

(1984). Article  CAS  Google Scholar  * 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_ 195, 387–396 (1993). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank S. Turk for technical

assistance and D.-B. Borza for help with figures. This work was supported by National Institutes of Health grant RO1- AI20662. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * School of

Biological Sciences, University of Missouri-Kansas City, Kansas City, Missouri, USA Corina M. Borza & Lindsey M. Hutt-Fletcher Authors * Corina M. Borza View author publications You can

also search for this author inPubMed Google Scholar * Lindsey M. Hutt-Fletcher View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS

Correspondence to Corina M. Borza or Lindsey M. Hutt-Fletcher. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. RIGHTS AND PERMISSIONS Reprints

and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Borza, C., Hutt-Fletcher, L. Alternate replication in B cells and epithelial cells switches tropism of Epstein–Barr virus. _Nat Med_ 8,

594–599 (2002). https://doi.org/10.1038/nm0602-594 Download citation * Received: 20 September 2001 * Accepted: 17 April 2002 * Issue Date: 01 June 2002 * DOI:

https://doi.org/10.1038/nm0602-594 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently

available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative