EBV Antigens

The major antigens of EBV include six EBV-associated nuclear antigens (EBNA, 1,2,3a,3b,3c,-leader protein (LP)), early antigen (EA), which comes in diffuse (D) and restricted (R) forms, viral capsid antigen (VCA), EBV-induced membrane antigen (MA), and latent membrane proteins (LMP) (2).

(8)

The six EBNA proteins constitute a family of EBV-associated nuclear antigens.  EBNA-1 is important for maintenance of the plasmid viral DNA in latently infected cells and in activation of viral DNA replication.  EBNA-1 is a 60 to 85-kDa polypeptide which contains a variable number of glycine-alanine repeats.  EBNA-1 is expressed in all EBV infected cells, but the other EBNAs are not.  In type-1 latency, EBNA-1 alone is expressed, which occurs in Burkitt's lymphoma.  In type-2 latency, LMP is also expressed.  This state is characteristic of NPC and EBV-positive Hodgkin's lymphomas (1). EBNA-2, with a molecular weight of 81 to 95-kDa, is essential for the immortalization of lymphocytes by EBV.  It is the first gene expressed, in conjunction with EBNA-LP, and serves as a master switch in those cellular and viral genes involved in transformation.  EBNA 3A (136kD), 3B (142kD), and 3C (147kD) are involved in   EBV transformation of primary     human B lymphocytes (1).

LMP1 interacts with tumor necrosis factor receptor-associated factor 1 to affect cell growth and death signaling pathways (1).  It immortalizes B cells by activating the apoptosis-antagonizing bcl-2 gene (7).

Early antigen (EA) appears before viral replication.  The diffuse component is found in the nucleus while the restricted component is in the cytoplasm.  Viral capsid antigen (VCA) appears after viral replication and constitutes the virion.  It is found in both the cytoplasm and the DNA (1).

EBV-induced membrane proteins (MA) include those of molecular weights 340-350kDa(gp350), 220kDA(gp220), 110kDa(gp110), and 85kDa(gp85).  gp350/220 binds to CD21 facilitating entry into the B lymphocyte by receptor-mediated endocytosis.   gp85 is homologous to the herpes simplex viral protein and is important in fusion of the virus to the cell membrane. gp85 also causes virus neutralization in the presence of complement.  gp110 resides mainly in the nuclear membranes and endoplasmic reticulum of infected cells (1).  Recent evidence of its participation in the ADCC reaction indicates its expression on the cell surface as well (4).  gp350 and gp85 can be targeted by virus-neutralizing antibodies.  gp350 evokes ADCC and T-cell mediated responses and inhibits viral release from the cell.  It is the most studied of the viral antigens in attempts for vaccine development (1).

Host Antibody Response

Most persons infected with EBV have elevated antibody titers to VCA and EA.  See the Epidemiology and Diagnosis sections of this site for specific responses associated with the various forms of infection.

Complement dependent neutralizing antibody is responsible for clearing infectious mononucleosis (1).

Host Cell-Mediated Response

During acute infection (infectious mononucleosis) EBV-specific CD8+ cells eliminate large numbers of infected B-cells from the body.  This response is most likely responsible for the symptoms of fever, lymphadenopathy, and splenomegaly.  The exaggerated T-cell response during mono probably reflects cytokine secretion by EBV-infected B-cells (6).

Auto-Immunity

The existence of  autoantibodies specific for the glycine-alanine repeat region of EBNA-1 has been observed.  Proliferation of specific B-cell clones during reactivation can lead to the production of autoantibodies.  Sairenji and Kurata write, "Autoimmune diseases, such as systemic lupus erythematosus, Sjogrens' syndrome, Grave's disease, and hepatitis, have been described following EBV infection" (1).

EBV is also known to invade T-cells, altering T-cell proliferation and development.  It is thought that EBV infection of immature thymocytes during maturation may alter selection and development.  In fact, the viral BALF-Z protein may be a homologue of the RAG protein and thereby alter T-cell gene rearrangements (6).

Immune System Exploitation

The EBV genome encodes a homologue of IL-10, v-IL-10, which shares many of the naturally occuring cytokine's biological activities.  IL-10 acts to inhibit the cell-mediated response (Th1) and upregulate antibody proliferation.  This enhances the growth of  EBV transformed cells (5).  B-cell growth factors and corresponding receptors such as CD23 are also upregulated (7).

Epstein-Barr virus LMP1 was found to mimic CD40 signals to induce extrafollicular B-cell differentiation.  However, unlike CD40, it blocks germinal center formation (3).  This could enhance virus-specific B-cell proliferation.

Antibodies to the virus envelope neutralize viral activity during acute stages via ADCC.  However, the latent EBV phases lack expression of VCA and most other viral antigens.  EBNA-1 is not affected by natural humoral or cell-mediated responses and persists in many oncogenic states.  The virus can remain in a latent state, hidden from the immune system.

                                                                                                                            [back to top]
 
 

References

1. Sairenji, T., Kurata, T.  "Immune responses to Epstein-Barr viral infection." Herpesviruses and Immunity.  Medveczky, P.G., Friedman, H., Bendinelli, M., eds. New York: Plenum, 1998; 191-206.
2. Niederman, J.C., Evans, A.S.  "Epstein-Barr Virus."  Viral Infections of Humans: Epidemiology and Control.  New York: Plenum, 1997.
3. Uchida, J., Yasui, T., Takaoka-Shichijo, Y., Muraoka, M., Kulwick, W.  Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses. Science 1999; 286: 300-303.
4. Jilg, W., Bogedain, C., Mairhofer, H., Gu, S.Y., Wolf, H.  The Epstein-Barr virus glycoprotein gp110 (BALF 4) can serve as a target for antibody-dependent cell-mediated cytotoxicity (ADCC). Virology 1994; 202(2): 974-977.
5. Stuart, A.D., Stewart, J.P., Arrand, J.R., Mackett, M.  The Epstein-Barr virus encoded cytokine viral interleukin-10 enhances transformation of human B lymphocytes.  Oncogene 1995, 11(9), 1711-1719.
6. Rouse, B.T., Atherton, S.S. "Immunopathology of herpesvirus infections." Herpesviruses and Immunity Medveczky, P.G., Friedman, H., Bendinelli, M. eds. New York: Plenum, 1998; 33-51.
7. Klein, G. "EBV and B cell lymphomas."  Herpesviruses and Immunity Medveczky, P.G., Friedman, H., Bendinelli, M. eds. New York: Plenum, 1998; 165-190.
8. Rickenson, A.B., Kieff, E. "Epstein-Barr Virus."  Fields Virology 3rd. Edition. Philadelphia: Lippincott, 1996; 2402.