Five others, the genes for cathepsin H, annexin VI (p68), serglycin proteoglycan core protein, CD44, and the myristylated alanine-rich protein kinase C substrate (MARCKS), are genes which were not previously known to be induced by EBV infection.
The signaling lymphocyte activation molecule (SLAM)-associated protein, SAP, was first identified as the protein affected in most cases of X-linked lymphoproliferative (XLP) syndrome, a rare genetic disorder characterized by abnormal responses to Epstein-Barr virus infection, lymphoproliferative syndromes, and dysgammaglobulinemia.
Therefore, the down-regulation of the SAP gene by ATF5 may represent a common mechanism for the pathogenesis of HPS that is associated with either Epstein-Barr virus infection or immune disorders with dysregulated T-cell activation.
Thus, loss of SAP function can lead to dysregulated immune responses characterized by the uncontrolled expansion and activation of T cells independent of EBV infection.
Deficiency of SAP (SLAM (signaling lymphocyte activation molecule)-associated protein) protein is associated with a severe immunodeficiency, the X-linked lymphoproliferative disease (XLP) characterized by an inappropriate immune reaction against Epstein-Barr virus infection often resulting in a fatal clinical course.
Epstein-Barr virus (EBV) infection was significantly more common in SAP-deficient 10/13 (76.9%) than XIAP-deficient 2/7 (28.6%) patients, as was hypogammaglobulinemia (10/13 (76.9%) vs. 1/7 (14.3%)).
Our results with BL derived cell lines suggest that the fate of the precursor cells is decided by the expression of the proapototic SAP and EBV infection.
The unique bimodal intracellular SAP protein expression indicated the presence of some residual SAP-positive T cells that are able to respond to persistent Epstein-Barr virus infection and could explain the relatively mild clinical phenotype of this patient.
This rare disorder of immunedysregulation presents typically after Epstein-Barr virus infection and results from defects in the SAP (SLAM associated protein) gene.
Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved.
Comparative MSP analysis of p14, p16 and p73 methylation, using 20 cases each of formalin-fixed and paraffin-embedded tissues of early GC with and without EBV infection, confirmed 2 types of methylation: global methylation with increased rates (p14 and p16) and specific methylation of p73 in EBV-associated GC.
Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression.
A downstream validation study confirmed frequent inactivating mutations or protein deficiency of ARID1A, which encodes a member of the SWI-SNF chromatin remodeling family, in 83% of gastric cancers with microsatellite instability (MSI), 73% of those with Epstein-Barr virus (EBV) infection and 11% of those that were not infected with EBV and microsatellite stable (MSS).
ARID1A mutation of GC was significantly associated with microsatellite instability (MSI) (OR = 24.5, P < 0.001) and EBV infection (OR = 2.6, P = 0.001).
Specifically, in nasopharyngeal carcinoma (NPC) tissues and the EBV-positive cell line C666-1, the miR-BART family accounted for more than 10% of all detected miRNAs, suggesting that these miRNAs have important roles in maintaining latent EBV infections and in driving NPC tumorigenesis.
In the present study, we proved that six forms of BARTs were present in EBV-positive cell lines and various tissue specimens with different EBV infection patterns.
Therefore, the down-regulation of the SAP gene by ATF5 may represent a common mechanism for the pathogenesis of HPS that is associated with either Epstein-Barr virus infection or immune disorders with dysregulated T-cell activation.
This review summarizes the current understanding of the relationship between EBV infection and the DDR transducers, including ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), and DNA-PK (DNA-dependent protein kinase), and discusses how EBV manipulates the DDR signaling pathways to complete the replication process of viral DNA during lytic reactivation.
NOD/SCID mice engrafted with human CD34(+) cells and reconstituted mainly with human B lymphocytes may serve as a useful xenograft model to study EBV infection and pathogenesis.