The potentially pathogenic effects of infection with Epstein-Barr virus (EBV), a B-lymphotropic agent with cell growth-transforming potential, are contained in healthy virus carriers by virus-specific cytotoxic T-lymphocyte (CTL) surveillance. The target antigens against which such CTL responses are directed are yet undefined, but the antigens probably derived from one or more of the EBV "latent" proteins constitutively expressed in virus-transformed B cells. We have analyzed target specificity of CTL responses from two EBV-immune donors that are preferentially reactive against autologous cells transformed with type A but not with type B virus isolates. Coding sequences for four EBV latent proteins with allelic polymorphism between A and B virus types--namely, the EBV nuclear antigens (EBNAs) EBNA 2, EBNA 3a, EBNA 3c, and EBNA leader protein--have been introduced into vaccinia virus vectors under control of vaccinia promoter P7.5 and used to express relevant EBNA proteins in appropriate target cells. Thus the CTL response from one donor has been mapped to type A EBNA 2 protein and from a second donor to type A EBNA 3a protein. Thereafter, a series of recombinant vaccinia viruses were constructed that carried specific internal deletions within the EBNA 2 type A coding sequence; by using these vectors, the above EBNA 2 type A-specific CTL response was shown to be directed against an epitope within a 100-amino acid fragment near the N terminus of the protein. This work clearly shows human CTL recognition of virus-coded nuclear antigens in the EBV system; moreover, it establishes an experimental approach that can be extended to all EBV latent proteins and to the more common CTL responses that cross-react against type A and type B virus isolates.

Human cytotoxic T-cell responses against Epstein-Barr virus nuclear antigens demonstrated by using recombinant vaccinia viruses.

Cancer in Organ Transplant Recipients

The Epstein-Barr virus nuclear antigen 2 (EBNA 2) shows serotype variation and two serologically distinct groups of viruses have been identified. These correspond to the two hybridization groups of viruses (A and B) that are distinguished by a highly substituted nucleic acid sequence in the middle of the open reading frame of the EBNA 2 gene. An epitope survey of the EBNA 2-coding region was carried out using a new prokaryotic expression vector tailored to express DNA fragments from the M13 sequencing libraries of the B95-8 (type A) and Jijoye (type B) prototype virus strains. Short overlapping stretches of EBNA 2 sequence were expressed as fusion proteins and used in Western blotting with human sera that contained serotype-specific antibodies. The type A-specific epitope was located between residues 378 and 435 of the B95-8 EBNA 2 polypeptide and the type B-specific epitope mapped between residues 390 and 454, at the carboxy terminus of the Jijoye polypeptide chain. All of the type-specific anti-EBNA 2 sera tested reacted with fusion proteins containing one or other of these epitopes. Despite the direct correlation between the hybridization and serological phenotypes, the type-specific epitopes appear to lie in the relatively conserved carboxy-terminal region of EBNA 2. There was no indication that the residues of the non-homologous region contributed to the formation of antibody-combining sites.

The type-specific epitopes of the Epstein-Barr virus nuclear antigen 2 are near the carboxy terminus of the protein.

Cellular immune responses to Epstein-Barr Virus (EBV)-associated antigens play an important role in the control of EBV-immortalized B lymphocytes. The nature of the antigens that serve as targets for these responses remains largely unknown. The purpose of the experiments reported here was to determine if virus-replication-associated antigens might function as targets for T-cell immunity with the emphasis on EBV-induced early antigen (EA) complex. Activated T-cell populations directed against this group of antigens would theoretically be effective in controlling the production of new virus progeny. Our results demonstrate that polypeptides associated with the EA complex do, in fact, induce the proliferation of memory T-cells from EBV-infected individuals irrespective of their serological status to the EA complex. The major polypeptide associated with the diffuse component of EA (EA-D) was notably effective in inducing a strong proliferative T-cell response. Cell lines established from EBV-infected individuals following continuous exposure to either p17 or p50 components of the EA complex over a 10- to 12-week period were composed primarily of CD4-positive T-cells, although CD8-positive cells also persisted for up to 9 weeks in culture. The data suggest that components of the EA complex might function as important target antigens in the immunosurveillance of EBV-infected cells.

Human T-cell recognition of Epstein-Barr virus-induced replication antigen complexes.

A limited set of viral gene products, the so-called “latent” proteins, have been identified as the probable target antigens in the induction of cellular immunity directed against Epstein-Barr virus (EBV) immortalized B cells (LCL)(1). These constitutively expressed proteins include EBV nuclear antigens (EBNA 1–3) (2–4) and a “latent” membrane protein (5,6).

Cell-Mediated Responses to Epstein-Barr Virus Lytic Antigens

Epstein-Barr (EB) virus isolates can be classified as type A or type B depending upon the identity of the virus-encoded nuclear antigen EBNA 2; the EBNA 2A and 2B proteins show limited amino-acid homology and induce largely non-cross-reactive antibody responses in humans. To examine whether EBNA 2 might also be a target for virus-specific cytotoxic T-cell responses (like “intracellular” antigens in other viral systems), normal B cells from non-immune donors of known HLA type were transformed in vitro with virus isolates either of type A (from the B95-8 and IARC-BL74 cell lines) or of type B (from the AG876 and IARC-BL16 cell lines) to provide a suitable panel of target cells. DNA hybridization with type-specific probes and immunoblotting with type-specific antisera confirmed the EBNA 2 type of the resident virus in the various in vitro transformants. These cells were then tested as targets for virus-specific cytotoxic T cells, the latter being prepared from type-A virus-infected donors by in vitro reactivation of memory cells from peripheral blood using autologous type-A virus-transformed cells as stimulators. Such effector cells lysed type-A virus-transformed and type-B virus-transformed target cells equally well, indicating that EBNA 2 (in particular that part of the protein which varies between virus types) seems not to be a dominant antigen for the induction of EB virus-specific cytotoxic responses.

Epstein-Barr virus-specific T-cell recognition of B-cell transformants expressing different EBNA 2 antigens.

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Epstein-Barr virus-specific T-cell recognition of B-cell transformants expressing different EBNA 2 antigens.