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HHV-6A infection induces expression of HERV-K18-encoded superantigen

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Abstract

Background

The human endogenous retrovirus K-18 (HERV-K18) encodes a superantigen that causes deregulation of the immune system. This provirus is transcriptionally silent, but can be induced by Epstein–Barr virus (EBV) infection and IFN-α treatment.

Objectives

Since the herpesvirus EBV induces HERV-K18 expression in human B cells, it was of interest to determine if other herpesviruses would have similar HERV-K18 transactivation properties. Human herpesvirus (HHV)-6A, a neurotropic virus associated with multiple sclerosis, was a logical candidate for these studies.

Study design

HSB2 cells (HHV-6-negative control), HSB2-ML cells (containing latent HHV-6A genome) and HSB2/HHV-6A cells (HSB-2 cells productively infected with HHV-6A) were compared for their level of HERV-K18 transcription, using quantitative RT-PCR.

Results

Latently infected HSB2-ML cells showed a significant increase in HERV-K18 RNA compared to the control cells. HERV-K18 expression was even greater in HSB2 cells productively infected with HHV-6A for 78 h.

Conclusion

These results imply that HHV-6A, either in latent form or during acute infection, directly transactivates HERV-K18. This HERV-K18 induction may be mediated through IFN-α that is produced by the HHV-6A-infected cells. The functional implications of superantigen expression are discussed.

Introduction

Several human endogenous retroviruses (HERVs) have been proposed to play a role in the pathogenesis of multiple sclerosis (MS), including HERV-W,1 MSRV,2 HERV-H3 and HERV-K18.4 We have shown that HERV-K18 encodes a superantigen,5 which is a class of proteins that causes deregulation of the immune system.6 This provirus is transcriptionally silent, but our laboratory has discovered that EBV infection5, 7 activates transcription of the env gene of HERV-K18. IFN-α treatment has also been shown to activate HERV-K18.8 Three alleles of HERV-K18 env have been documented, K18.1, K18.2, K18.3, and the gene products from all three alleles have superantigen activity.5, 8 They are predicted, however, to have different biochemical and functional characteristics.5 By HERV-K18 allele typing of two large cohorts of MS patients and controls, we recently established that MS patients are more likely to have HERV-K18.3 compared to healthy controls.4 Thus, K18.3 represents a risk factor in MS.

Our hypothesis is that HERV-K18 is transactivated not only by EBV, but also by other herpesviruses. Here, we show that HHV-6A (GS strain),9 either in latent form or during acute infection, induces HERV-K18 mRNA expression in HSB2 cells, an immature T-cell line. Thus, HHV-6A infection associated with HERV-K18 expression could also represent a risk factor for MS, which may or may not explain the association with HHV-6A that has been proposed by others.10, 11, 12, 13

Section snippets

Methods

The human T cell line, HSB2, and a variant, HSB2-ML, which is latently infected with HHV-6A variant prototype GS,9 were grown in tissue culture. HSB2 cells were also acutely infected with HHV-6A GS (HSB2/HHV6) for 48 or 72 h. Productive infection was monitored by staining the cells for early antigen at 48 h (26%), as well as for p41 and p150 expression at 72 h (67% and 18%, respectively). The cells were harvested and mRNA was isolated using the PAXgene Blood RNA kit (Qiagen, Cat#. 762164). The

Results

The data presented in Fig. 1 demonstrate that HHV-6A transactivates the transcription of HERV-K18, both during latent (HSB2-ML) and acute (HSB2/HHV6) HHV-6A infection. Thus, we can conclude that HHV-6A is likely to lead to superantigen production, similar to EBV, although we have not yet proven the former.

Discussion

Since we have already established that HERV-K18 is a risk factor in MS,4 the results presented here may provide an explanation for this association. Many studies have noted a correlation between the incidence of MS and HHV-6A.10, 11, 12, 13, 15 There are two distinct HHV-6 variants, A and B16; HHV-6A is more neurotropic than HHV-6B,17, 18 and treatment with IFN-β reduces the detection of HHV-6 in sera and PBMCs.19 HHV-6A active replication in MS patients may be associated with polymorphisms of

Acknowledgements

We are indebted to Kristin Loomis for suggesting these studies and organizing the collaboration between the Huber lab and the HHV-6 Foundation. We thank Courtney Devin for editorial assistance. This work was supported by a pilot grant from the HHV-6 Foundation.

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