Epstein-Barr Virus Transactivates the Human Endogenous Retrovirus HERV-K18 that Encodes a Superantigen

Sutkowski, Natalie; Conrad, Bernard; Thorley‐Lawson, David A.; Huber, Brigitte

doi:10.1016/s1074-7613(01)00210-2

Cited by 273 publications

(243 citation statements)

References 45 publications

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“…IL-1 and tumor necrosis factor α (TNFα) stimulate, while IFN-γ inhibits transcription of HERV-R in human vascular endothelial cells [86]. IFN-α induces expression of HERV-K18.1 env, which acting as a superantigen, causes Vβ7- [87] or Vβ13-specific T-cell expansions [88]. Steroids have long been known to induce expression and virion formation from ERV in the mouse [89].…”

Section: Immunomodulation By Ervmentioning

confidence: 99%

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

et al. 2008

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Genetic and environmental factors are believed to influence development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERV) correspond to the integrated proviral form of infectious retroviruses, which are trapped within the genome due to mutations. ERV represent a key molecular link between the host genome and infectious viral particles. ERV-encoded proteins are recognized by antiviral immune responses and become targets of autoreactivity. Alternatively, ERV protein may influence cellular processes and the life cycle of infectious viruses. As examples, the HRES-1 human ERV encodes a 28-kDa nuclear autoantigen and a 24-kDa small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a nuclear autoantigen recognized by crossreactive antiviral antibodies, while HRES-1/Rab4 regulates surface expression of CD4 and the transferrin receptor (TFR) through endosome recycling. Expression of HRES-1/Rab4 is induced by the tat gene of HIV-1, which in turn down-regulates expression of CD4 and susceptibility to reinfection by HIV-1. CD4 and the TFR play essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. T-cell receptorζ (TCRζ) chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced lck and TCRζ chain levels. HRES-1 is centrally located on chromosome 1 at q42 relative to lupus-linked microsatellite markers and polymorphic HRES-1 alleles have been linked to the development of SLE. 1q42 is one of the three most common fragile sites in the human genome, and is inducible by DNA demethylation, a known mechanism of retroviral gene activation. Molecular mimicry and immunomodulation by a ERV, such as HRES-1, may contribute to self-reactivity and abnormal Tand B-cell functions in SLE. (Table I). HERVs are commonly designated as HERV followed by a single letter amino acid code corresponding to a tRNA. The 3′ terminus of tRNA is predicted to initiate reverse transcription by annealing to an 18 nucleotide long primer-binding site (PBS) at the 5′ LTR. While expression of murine ERV can lead to production of infectious virus and cause viremia, no production of infectious virion has been documented by HERV. High copy number of most ERV families makes it difficult to distinguish which members of a group are expressed. Although, no single provirus with intact LTRs and uninterrupted gag, pol, and env ORFs has been identified, the HERV-K ERV, as a family, has been shown to encode gag HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript the LTR region, is functionally analogous to the HIV-1 rev and HTLV-I/II rex proteins. HERV-K rev binds to both the nuclear export factor Crm1 and to a cis-acting viral RNA to activate nuclear export of unspliced RNAs [39]. Alternatively, the HERV-K LTR is also recognized by HIV-1 rev, suggesting a potential interaction between these exogeneous a...

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Section: Immunomodulation By Ervmentioning

confidence: 99%

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

et al. 2008

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“…␥-Herpesviruses such as EBV and murine ␥-herpesvirus 68 (MHV-68) show a SAg-like activity: EBV activates a host SAg on infection (51). MHV-68 shows a V␤4-specific MHC unrestricted oligoclonal CD8 T cell stimulation (52).…”

Section: Different Strategies Leading To Similar Outcomes: Mmtv Vs Ebvmentioning

confidence: 99%

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

Finke

Luther²,

Acha‐Orbea³

2002

Proc. Natl. Acad. Sci. U.S.A.

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Mouse mammary tumor virus (MMTV) infection establishes chronic germinal centers and a lifelong neutralizing Ab response. We show that removal of the draining lymph node after establishment of the germinal center reaction led to complete loss of neutralizing Abs despite comparable infection levels in peripheral lymphocytes. Importantly, in the absence of neutralization, only the exocrine organs mammary gland, salivary gland, pancreas, and skin showed strikingly increased infection, resulting in accelerated mammary tumor development. Induction of stronger neutralization did not influence chronic infection levels of peripheral lymphoid organs but strongly inhibited mammary gland infection and virus transmission to the next generation. Taken together, we provide evidence that a tight equilibrium in virus neutralization allows limited infection of exocrine organs and controls cancer development in susceptible mouse strains. These experiments show that a strong neutralizing Ab response induced after infection is not able to control lymphoid MMTV infection. Strong neutralization, however, is capable of blocking amplification of mammary gland infection, tumor development, and virus transmission to the next generation. The results also indicate a role of neutralization in natural resistance to MMTV infection.

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“…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).…”

mentioning

confidence: 99%

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

Sutkowski

Chen

Calderón

et al. 2004

J Virol

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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...

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Epstein-Barr Virus Transactivates the Human Endogenous Retrovirus HERV-K18 that Encodes a Superantigen

Cited by 273 publications

References 45 publications

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

The role of neutralizing antibodies for mouse mammary tumor virus transmission and mammary cancer development

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

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