Epstein-Barr Virus (EBV) Nuclear Antigen (EBNA)-4 Mutation in EBV-Associated Malignancies in Three Different Populations

Abstract

Different ethnic groups with a high human leukocyte antigen (HLA)-A11 prevalence have been shown to experience a high rate of Epstein-Barr virus (EBV)infection , EBV-associated malignancies , and EpsteinBarr nuclear antigen (EBNA)-4 mutations. The epitopes 399-408 and 416-424 of EBNA-4 are major antigenic epitopes that elicit an HLA-A11 cytotoxic T lymphocyte (CTL) response to EBV infection. Mutations selectively involving one or more nucleotide residues in these epitopes affect the antigenicity of EBNA-4 , because the mutant EBV strains are not recognized by the HLA-A11-restricted CTLs. To investigate these mutations in common EBV-associated malignancies occurring in different populations, we studied the mutation rate of epitopes 399-408 and 416-424 of EBNA-4 in 25 cases of EBV-associated Hodgkin's disease (HD) , nine cases of AIDS-related non-Hodgkin's lymphoma , and 37 cases of EBV-associated gastric carcinoma (GC) from the United States, Brazil , and Japan. We found one or more mutations in these two epitopes in 50% (6/12) of United States HD, 15% (2/13) of Brazilian HD , 50% (6/12) United States GC and 28% (7/25) Japanese GC , and 22% (2/9) of United States AIDS-lymphoma. Similar mutations were found in 30% (3/10) of United States reactive, 0% (0/6) of Brazilian reactive , and 25% (2/8) Japanese reactive tissues. The most frequent amino acid substitutions were virtually identical to those seen in previously reported isolates from EBV-associated nasopharyngeal carcinomas and Burkitt's lymphomas occurring in high prevalence HLA-A11 regions. However , only 2/28 (7%) mutations occurred in HLA-A11-positive patients. Our studies suggest that: 1) EBNA-4 mutations are a common phenomenon in EBV-asso- Epstein-Barr virus (EBV), a member of the human herpesvirus family, is ubiquitous worldwide, with more than 90% of adults having evidence of past EBV infection. EBV-specific cytotoxic T lymphocytes (CTLs) are found in virtually all healthy virus-carrying individuals.

Epstein-Barr Virus Nuclear Antigen (EBNA)-1 Carboxy-Terminal and EBNA-4 Sequence Polymorphisms in Nasal Natural Killer/T-Cell Lymphoma in the United States

“…Mutations within epitopes 399 -408 and 416 -424, which have been shown to be the major immunogenic epitopes of the HLA-A11-restricted CTL response to EBV infection, were equally as common (25%) in HLA-A11-negative and HLA-A11-positive cases. Most (70%) of the EBNA-4 mutations detected in this study were at residues 399, 400, 417, and 424, all of which were previously identified hot spots showing similar amino acid mutations in other EBV-associated tumors (Burrows et al, 1996;Chu et al, 1999;de Campos-Lima et al, 1994).…”

“…Subsequent studies, however, support the notion that variations in EBNA-4 sequence are primarily related to geographic variations and are unrelated to HLA-A11 status, being just as common in populations with a low HLA-A11 frequency (Burrows et al, 1996;Khanna et al, 1997). EBNA-4 mutations have also been identified commonly in EBVassociated Hodgkin's disease, gastric carcinoma, and AIDS-related lymphomas from the U.S., Brazil, and Japan and were unrelated to HLA-A11 status (Chu et al, 1999). No data have been published on EBNA-4 in NL to our knowledge.…”

Epstein–Barr Virus Strain Variation

“…For example (Chu et al 1999), polymorphisms of EBNA-3B (called EBNA4 in that publication) were found to be frequent in EBV-associated Hodgkin's lymphoma, gastric carcinoma and AIDS-lymphoma but not related to patients' HLA-A11 status. Sequence variation in EBNA-3B is now being reexamined since it has been realised that EBNA-3B acts as a tumour suppressor gene (White et al 2012).…”

Papel dos genes latentes do vírus Epstein-Barr na oncogênese

“…Essa família é constituída por três proteínas: EBNA3A, EBNA3B (EBNA4) e EBNA3C (EBNA6) 27,28 . Tem sido demonstrado que as proteínas EBNA3A e -3C são fundamentais na transformação de linfócitos B in vitro, enquanto que a participação do EBNA3B parece ser dispensável 25 .…”