Epstein‐Barr virus lytic cycle involvement in diffuse large B cell lymphoma

Abstract

Epstein-Barr virus (EBV)-mediated B cell transformation is achieved predominantly through the action of latent proteins, but recent evidence suggests that lytic EBV replication has also a certain pathogenic role in lymphomagenesis, at least in the early phases of cell transformation. Particularly, in diffuse large B cell lymphoma (DLBCL), the EBV lytic cycle is by and large unexplored, so to disclose lytic cell contribution to lymphomagenesis, our aim was to evaluate viral early and late lytic gene expression in relation to several immune response markers in a series of EBV+ DLBCL from Argentina. An unexpected number of cells expressed lytic transcripts, being transcribed at the BZLF1, BHRF1, and BLLF1 locus, by real-time quantitative polymerase chain reaction. This lytic antigen expression was confirmed by immunohistochemical staining for BMRF1 early lytic protein, and a positive correlation between lytic and latent genes was confirmed, revealing a close link between their expressions in EBV+ DLBCL pathogenesis. Remarkably, BZLF1 displayed a negative correlation with CD4 cell counts, and this could be in part justified by the restriction of antigen presentation previously reported. The direct correlation for the late lytic gene BLLF1 and IFNγ in this series could represent a specific response directed towards this antigen. Interleukin 10 transcripts also displayed a positive correlation with lytic expression, indicating that regulatory mechanisms could be also involved on EBV-associated DLBCL pathogenesis in our series. Complete lytic reactivation in EBV-positive tumours could potentially kill EBV-positive malignant cells, providing a tool to promote tumour cell killing mediated by EBV as a complementary treatment strategy.

EBV Positive Diffuse Large B Cell Lymphoma and Chronic Lymphocytic Leukemia Patients Exhibit Increased Anti-dUTPase Antibodies

“…However, a recent study demonstrated that therapy related to immunosuppression in patients with CLL resulted in EBV reactivation, which drove RS and the formation of the ABC subtype DLBCL in some patients [ 17 ]. This study as well as a recent study of DLBCL [ 18 ] has suggested that products of lytic EBV may contribute to the development of these malignancies, but additional studies need to be performed.…”

“…A recent study demonstrated that immediate early and early EBV proteins expressed during lytic replication of EBV are expressed in some tumor cells in patients with EBV + DLBCL and that antibodies against these proteins are detected in patients’ sera. This led the investigators to propose that products from lytic/abortive lytic replication may contribute to tumor growth and survival [ 18 ]. Our previous studies have demonstrated that the EBV-dUTPase protein induces IL-6 in primary dendritic cells and PBMCs [ 46 , 47 , 48 ].…”

The Immunomodulatory Capacity of an Epstein-Barr Virus Abortive Lytic Cycle: Potential Contribution to Viral Tumorigenesis

“…Experiments with mutant knockout viruses in one or both of these genes revealed redundant activities but an absolute requirement for at least one of them to transform primary B cells [ 35 ]. BHRF1 and BALF1 are highly expressed during the pre-latent abortive lytic cycle [ 35 ], but also their expression has been detected in BLs [ 14 , 36 ], DLBCLs [ 37 ] and in a subset of EBV associated gastric cancers (EBVaGC) [ 38 , 39 ].…”

The Role of the Epstein-Barr Virus Lytic Cycle in Tumor Progression: Consequences in Diagnosis and Therapy

“…Many articles have previously mentioned the existence of the lytic cycle, especially in transplant patients with PTLD. Studies conducted on EBV lytic proteins, especially the IE proteins like ZEBRA, in patients with PTLD or HIV-associated NHL are still scarce, mostly relating to the role of EBV proteins and gene products in neoplastic tissues [18,40,[90][91][92][93][94][95]. It must be pointed out that several authors exploring BZLF1 transcripts in the peripheral blood lymphocytes (PBL) of PTLD patients demonstrated that both a high EBV genome number and strong BZLF1 mRNA expression are sensitive markers of EBV-related PTLD [96].…”