Epstein-Barr Virus Latent Membrane Protein LMP-2A Is Sufficient for Transactivation of the Human Endogenous Retrovirus HERV-K18 Superantigen

Abstract

Superantigens are microbial proteins that strongly stimulate T cells. We described previously that the Epstein-Barr virus (EBV) transactivates a superantigen encoded by the human endogenous retrovirus, HERV-K18. We now report that the transactivation is dependent upon the EBV latent cycle proteins. Moreover, LMP-2A is sufficient for induction of HERV-K18 superantigen activity.Superantigens are pathogen-derived proteins that elicit a strong primary T-cell response from the host (reviewed in references 25 and 27). Superantigens are presented to T cells by major histocompatibility complex (MHC) class II molecules on antigen-presenting cells. They differ from conventional peptide antigens by binding solely to the V␤ portion of the T-cell receptor (TCRBV) outside of the peptide-binding groove, thus forming a bridge between the T cell and the antigen-presenting cell (29). This bridging transduces a signal to the T cell, causing it to secrete cytokines that can further activate surrounding T cells. The hallmark of a superantigen response is the rapid and strong primary T-cell activation, which is MHC class II dependent and TCRBV restricted. In addition, antigen processing into peptides is not required. Both bacteria and viruses encode superantigens. The bacterial superantigens are mainly enterotoxins, which are secreted and bind externally to MHC class II molecules for presentation (34). In contrast, viral superantigens are glycosylated proteins that are endogenously produced in the infected cells.There are three families of viruses that are associated with superantigen or superantigen-like activity: Retroviridae, Rhabdoviridae, and Herpesviridae. Retroviral superantigens were first depicted in the B-type virus group in mouse mammary tumor viruses and are found in both infectious mouse mammary tumor viruses and endogenous proviruses (14,18,39,63). It has been previously shown that the env gene of HERV-K18, a defective human endogenous provirus located on chromosome 1, encodes a superantigen activity (51, 52). The HERV-K family is closely related to the B-type retroviruses based on amino acid similarity in the reverse transcriptase gene (48). HERV-K18 is a relatively recent integrant in the genome, as it is found in Old World primates but not in New World primates, indicating that it was acquired subsequent to the evolutionary divergence of these species (28). A few years ago, it was reported that Epstein-Barr virus (EBV) is associated with TCRBV13-specific superantigen activity, which is MHC class II dependent and not due to a recall antigen response (53). More recently, it was demonstrated that the superantigen activity is due to EBV transactivation of HERV-K18 env (52). We show here that this activity is dependent upon the major EBV latent gene transactivator EBNA-2, which upregulates most of the other EBV latent genes, all of which have the ability to transactivate host cell genes. In accordance with this finding, we show that the EBV latent membrane protein LMP-2A is sufficient for transactivation of HERV-K18 env.E...

Cutting Edge: Epstein-Barr Virus Transactivates the HERV-K18 Superantigen by Docking to the Human Complement Receptor 2 (CD21) on Primary B Cells

“…Subsequently, we demonstrated that two EBV-encoded proteins, LMP-2A and LMP-1, are each responsible for transactivating HERV-K18 env during latency (11). In the present study we have shown that HERV-K18 env is transactivated as early as when EBV first docks to hCD21 on its host cell, before the establishment of latency.…”

“…Efforts to understand how EBV transactivates the HERV-K18 superantigen revealed that LMP-2A and LMP-1 each contributes to the induction of the superantigen activity in latently infected cells in vitro (11). To further understand the biological significance of the superantigen, the status of the HERV-K18 env transcript was investigated during the earlier stages of the EBV infection process before the establishment of latency.…”

Repeated Recruitment of LTR Retrotransposons as Promoters by the Anti-apoptotic Locus NAIP During Mammalian Evolution

“…For example, activation of NAIP via an LTR promoter may provide an avenue for germ cells to escape transitory, stress-induced apoptotic signals. LTR promoters may be particularly responsive to upregulation by cellular stresses since it has been shown that activation of human and mouse ERV LTRs can occur following stresses such as viral infection [54][55][56] and UV irradiation [57,58]. Various IAPs are expressed in human [59,60], mouse [61], and rat [62,63] germ cells or their progenitors, and it has been reported that Naip expression plays a role in mouse oocyte viability [61].…”

Des séquences rétrovirales endogènes dans le génome humain peuvent jouer un rôle physiologique ou pathologique

“…Les récepteurs des fragments du complément L'engagement des récepteurs membranaires des fragments du complément, notamment le C3b, semble aussi jouer un rôle important dans la transactivation d'HERV. En effet, les gènes de latence d'EBV, LMP (latent membrane protein)-1 et LMP-2A, qui codent des protéines membranaires impliquées dans la survie des lymphocytes B infectés [16], peuvent transactiver HERV-K18 via une interaction avec le CD21 ou CR2 (complement receptor type 2), récepteur du C3d exprimé par les lymphocytes B [17]. Cette transactivation étant quasi immédiate après l'entrée d'EBV dans les cellules, il n'est pas nécessaire qu'il y ait une réplication virale.…”