Superantigens (SAgs) are proteins produced by pathogenic microbes to elicit potent, antigen-independent T cell responses that are believed to enhance the microbes' pathogenicity. Here we show that the human lymphotropic herpesvirus Epstein-Barr virus (EBV) transcriptionally activates the env gene of an endogenous retrovirus, HERV-K18, that possesses SAg activity. SAg activity was demonstrated by MHC class II dependent preferential activation of TCRVB13 T cells in response to murine B cells transfected with the HERV-K18 env gene. This is a unique demonstration of a pathogen inducing a host-encoded Sag and accounts for the previously described EBV associated Sag activity. The T cell activation elicited by the Sag could play a central role in EBV infection and associated diseases.
More than 90% of adults are latently infected with Epstein-Barr virus (EBV), the causative agent of infectious mononucleosis, a self-limiting lymphoproliferative disease characterized by extensive T cell activation. Reactivation of this herpesvirus during immunosuppression is often associated with oncogenesis. These considerations led us to analyze the early events that occur after exposure of the immune system to EBV. Strong major histocompatibility complex (MHC) class II- dependent but not MHC-restricted, T cell proliferation was observed in vitro in response to autologous, lytically infected EBV-transformed B cells. By measuring the appearance of the early activation marker CD69 on individual T cell V beta subsets, we could demonstrate selective activation of human V beta 13- T cells. This was confirmed with murine T cell hybridomas expressing various human BV genes. While EBV- Burkitt's lymphoma cells were nonstimulatory, they induced V beta- restricted T cell activation after EBV infection. EBV specific activation was also demonstrated in cord blood cells, excluding a recall-antigen response. Thus, all of the characteristics of a superantigen-stimulated response are seen, indicating that induction of the EBV lytic cycle is associated with the expression of a superantigen in B cells. A model is presented proposing a role for the superantigen in infection, latency, and oncogenesis.
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...
Oropharyngeal cancer has demonstrated a steady increase in incidence over the past 20 years in contrast to declining numbers of head and neck squamous cell carcinoma (HNSCC) overall. Recent evidence has found that high-risk strains of human papillomavirus (HPV) are the likely cause of the changing epidemiology of oropharyngeal cancer. HPV-associated oropharyngeal cancer has a molecular, epidemiological, and clinical profile that is distinct from non-HPV HNSCC. Clinicians managing oropharyngeal HNSCC need to be aware of differences in the HPV HNSCC population which may impact treatment outcomes. Testing of HNSCC tumor tissue for HPV using validated and precise techniques should be performed when feasible.
EBV encodes latent membrane protein (LMP)-2A that functions as a homologue of the activated BCR. We have previously shown that LMP-2A transactivates a human endogenous retrovirus, HERV-K18, in infected B-lymphocytes. The Env protein of HERV-K18 encodes a superantigen that strongly stimulates a large number of T cells. To delineate the mechanism through which LMP-2A transactivates HERV-K18 env, we tested a panel of tyrosine mutants of LMP-2A in a murine B lymphoma that stably harbors HERV-K18. Our analysis revealed that the immunoreceptor tyrosine-based activation motif (ITAM) of LMP-2A is important for HERV-K18 env transactivation. ITAM contains 2 tyrosines that initiate signaling cascades when both residues are phosphorylated. However, in our study, single-tyrosine mutants of ITAM still retained full induction of HERV-K18 env. After truncating 25 kb of genomic sequence downstream of HERV-K18, LMP-2A failed to transactivate HERV-K18 env. Thus, an LMP-2A-inducible element is located downstream of HERV-K18.
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