Epstein-Barr Virus Evasion of CD8(+) and CD4(+) T Cell Immunity via Concerted Actions of Multiple Gene Products

Semin Cancer Biol. 2008 Dec;18(6):397-408. doi: 10.1016/j.semcancer.2008.10.008. Epub 2008 Oct 25.

Abstract

Upon primary infection, EBV establishes a latent infection in B cells, characterized by maintenance of the viral genome in the absence of viral replication. The Epstein-Barr Nuclear Antigen 1 (EBNA1) plays a crucial role in maintenance of the viral DNA episome and is consistently expressed in all EBV-associated malignancies. Compared to other EBV latent gene products, EBNA1 is poorly recognized by CD8(+) T lymphocytes. Recent studies are discussed that shed new light on the mechanisms that underlie this unusual lack of CD8(+) T cell activation. Whereas the latent phase is characterized by the expression of a limited subset of viral gene products, the full repertoire of over 80 EBV lytic gene products is expressed during the replicative phase. Despite this abundance of potential T cell antigens, which indeed give rise to a strong response of CD4(+) and CD8(+) T lymphocytes, the virus can replicate successfully. Evidence is accumulating that this paradoxical situation is the result of actions of multiple viral gene products, inhibiting discrete stages of the MHC class I and class II antigen presentation pathways. Immediately after initiation of the lytic cycle, BNLF2a prevents peptide-loading of MHC class I molecules through inhibition of the Transporter associated with Antigen Processing, TAP. This will reduce presentation of viral antigens by the large ER-resident pool of MHC class I molecules. Synthesis of new MHC class I molecules is blocked by BGLF5. Viral-IL10 causes a reduction in mRNA levels of TAP1 and bli/LMP2, a subunit of the immunoproteasome. MHC class I molecules present at the cell surface are downregulated by BILF1. Also the antigen presenting capacity of MHC class II molecules is severely compromised by multiple EBV lytic gene products, including gp42/gH/gL, BGLF5, and vIL-10. In this review, we discuss how concerted actions of these EBV lytic proteins result in highly effective interference with CD8(+) and CD4(+) T cell surveillance, thereby providing the virus with a window for undisturbed generation of viral progeny.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • ATP-Binding Cassette Transporters / immunology
  • ATP-Binding Cassette Transporters / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Cytokines / immunology
  • Cytokines / metabolism
  • Deoxyribonucleases / immunology
  • Deoxyribonucleases / metabolism
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Infections / virology
  • Epstein-Barr Virus Nuclear Antigens / genetics*
  • Epstein-Barr Virus Nuclear Antigens / immunology
  • Epstein-Barr Virus Nuclear Antigens / metabolism
  • Glycoproteins / immunology
  • Glycoproteins / metabolism
  • Herpesvirus 4, Human / genetics*
  • Herpesvirus 4, Human / immunology
  • Humans
  • Immunity
  • Receptors, G-Protein-Coupled / immunology
  • Receptors, G-Protein-Coupled / metabolism
  • Viral Proteins / immunology
  • Viral Proteins / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • BILF1 protein, Epstein-Barr virus
  • BZLF2 protein, Herpesvirus 4, Human
  • Cytokines
  • Epstein-Barr Virus Nuclear Antigens
  • Glycoproteins
  • Receptors, G-Protein-Coupled
  • Viral Proteins
  • transporter associated with antigen processing (TAP)
  • Deoxyribonucleases
  • deoxyribonuclease, Epstein-Barr virus