Epstein-Barr Virus Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication in Primary Effusion Lymphomas

Abstract

virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), also called human herpesvirus 8, are members of the human gammaherpesviruses and are associated with a variety of human malignancies. EBV is an important cause of lymphomas in severely immunocompromised persons, especially patients with AIDS and organ-transplant recipients (46,61,62,64,66). KSHV is believed to be the etiological agent of Kaposi's sarcoma (16,18,60) and is implicated in the pathogenesis of AIDS-associated primary effusion lymphoma (PEL), also called body cavity-based lymphoma, and multicentric Castleman's disease (23,60,86).Like other herpesviruses, EBV and KSHV go through both latency and lytic replication cycles. The KSHV replication and transcription activator (K-RTA) is necessary and sufficient for the switch from latency to lytic replication in KSHV (23,86,88). K-RTA is a sequence-specific DNA-binding protein that regulates many subsequently expressed viral genes (38,56,69,70,75,91,97). Also, K-RTA can interact with other factors to modulate its transcription potential (39,40,(51)(52)(53).EBV latent membrane protein 1 (LMP-1) is required for EBV transformation of primary B cells and establishment of EBV latency in vitro and is believed to play similar roles in EBV-associated tumor cells in vivo (45, 47). LMP-1 is an integral membrane protein and acts as a constitutively active receptor-like molecule that does not need a ligand (30,36,46,54). LMP-1 activates a variety of cellular genes that enhance cell survival and adhesive, invasive, angiogenic, and antiviral potential (31, 41, 59, 81-83, 87, 90, 94, 95).Interestingly, the majority of PELs are harboring both EBV and KSHV (13,14,42,68). In order to understand their contributions to the pathogenesis of PEL, it is important to address how EBV and KSHV interact with each other and affect biological properties of the cell and the viruses. PELs harboring two viruses have higher oncogenic potential (76), suggesting potential interactions between EBV and KSHV. This report describes a molecular interaction between EBV and KSHV, i.e., KSHV K-RTA potentiates EBV latency via induction of EBV LMP-1 and uses LMP-1 to curb KSHV lytic replication. These data suggest that the coinfection of EBV and KSHV in the majority of body cavity-based lymphomas might not be a coincidence: the presence of EBV is one of the strategies that KSHV uses for the maintenance of its latency. This report should be applicable to both KSHV and EBV studies in the majority of AIDS-associated PELs. MATERIALS AND METHODSCell culture, plasmids, adenoviruses, and antibodies. All cell lines used in this study and their properties are listed in Table 1. Expression plasmids for K-RTA (pCMV50) and the recombinant adenoviruses for green fluorescence protein (GFP) (AdGFP) and K-RTA (AdRTA) were a gift from Byrd Quinlivan (71).

Identification and Characterization of the Product Encoded by ORF69 of Kaposi's Sarcoma-Associated Herpesvirus

“…EBV and KSHV coinfect the majority of PEL cell lines, and molecular interactions between the two viruses have previously been reported (52). Whether these interactions might be relevant for the pathogenesis of EBV-and KSHV-associated diseases deserves further study.…”

Convergence of Kaposi's Sarcoma-Associated Herpesvirus Reactivation with Epstein-Barr Virus Latency and Cellular Growth Mediated by the Notch Signaling Pathway in Coinfected Cells

“…12). Previous publications have revealed negative, reciprocal feedback between KSHV and EBV in dually infected cells (33,50,69). Most notably, LMP-1 expression inhibits KSHV Rta expression and reactivation (Fig.…”

Virus proteins similar to human proteins as possible disturbance on human pathways

“…• hsa05168 Herpes simplex infection-Homo sapiens (human) (7) • hsa05161 Hepatitis B-Homo sapiens (human) (6) • hsa05162 Measles-Homo sapiens (human) (6) • hsa04620 Toll-like receptor signaling pathway-Homo sapiens (human) (6) • hsa05160 Hepatitis C-Homo sapiens (human) (6 • hsa04520 Adherens junction-Homo sapiens (human) (2) • hsa04120 Ubiquitin mediated proteolysis-Homo sapiens (human) (2) Except hsa05203 Viral carcinogenesis, hsa04060 Cytokine-cytokine receptor interaction, hsa05200 Pathways in cancer, hsa04120 Ubiquitin mediated proteolysis, and hsa04144 Endocytosis, all of which are collections of pathways and difficult to interpret as a protein interaction network, the obtained pathways are worth further analysis and some of them already show the relationships with cancers, such as hsa05169 Epstein-Barr virus infection (Xu et al 2007), hsa05166 HTLV-I infection (Veyssier-Belot et al 1990) as well as hsa05168 Herpes simplex infection (Bustamante and Wade 1991), hsa05161 Hepatitis B (Xie et al 2011), hsa05160 Hepatitis C (McGivern and Lemon 2011) and hsa04064 NF-kappa B signaling pathway (Kilger et al 1998).…”