BACKGROUND: To understand whether the association between Epstein-Barr Virus (EBV) and gastric cancer (GC) has any role in loss of surface expression of human lymphocyte antigen (HLA) class I, the authors analyzed locus-specific transcriptional expression of HLA-A, HLA-B, HLA-C, and HLA-E along with other HLA-associated molecules (beta2-microglobulin [beta2M], cellular latent membrane protein [LMP], and transporter associated with antigen presentation [TAP]) in EBV-associated, primary GC (EBVaGC) and EBV-negative GC (EBVnGC) tissues. METHODS: Approximately 20 EBVaGC tissues and 40 EBVnGC tissues and their corresponding normal tissues were used in the study. The presence of EBV in GC was established by EBV-encoded small RNA in situ hybridization analysis and BamHI W polymerase chain reaction (PCR) analysis. Transcriptional expression of viral LMP2A and several HLA class I genes were analyzed by reverse transcriptase (RT)-PCR. Surface expression levels of HLA class I proteins in cancer samples along with their normal counterparts also were quantified by flow cytometry. RESULTS: The RT-PCR data suggested selective down-regulation of the HLA-A/HLA-B locus along with over-expression of HLA-E transcripts in EBVaGC (P < .05). This was confirmed further by the flow-cytometric studies using antibodies to HLA-ABC and HLA-E. Among the accessory molecules, LMP7 transcript was down-regulated in a number of EBVaGC tissues compared with EBVnGC. CONCLUSIONS: The current results suggested that the establishment of EBV latent infection in gastric tissues allows malignant cells to avoid the immune surveillance of both cytotoxic T-lymphocytes and natural killer cells by regulating the differential expression of HLA class I molecules. 2006 American Cancer Society