Short communicationHHV-6A infection induces expression of HERV-K18-encoded superantigen
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.
References (22)
- et al.
Epstein–Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen
Immunity
(2001) - et al.
Interferon-alpha-induced endogenous superantigen. A model linking environment and autoimmunity
Immunity
(2001) - et al.
Clinical parameters and HHV-6 active replication in relapsing-remitting multiple sclerosis patients
J Clin Virol
(2006) - et al.
Environment-gene interaction in multiple sclerosis: human herpesvirus 6 and MHC2TA
Hum Immunol
(2007) - et al.
Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis
Proc Natl Acad Sci USA
(1997) - et al.
Multiple sclerosis-associated retrovirus and MS prognosis: an observational study
Neurology
(2002) Human herpesviruses in MS
Int MS J
(2007)- et al.
Human endogenous retrovirus-K18 Env as a risk factor in multiple sclerosis
Mult Scler
(2008) - et al.
The staphylococcal enterotoxins and their relatives
Science
(1990) - et al.
Epstein–Barr virus latent membrane protein LMP-2A is sufficient for transactivation of the HERV-K18 superantigen
J Virol
(2004)
Differential tropism of human herpesvirus 6 (HHV-6) variants and induction of latency by HHV-6A in oligodendrocytes
J Neurovirol
Cited by (60)
Interplay between activation of endogenous retroviruses and inflammation as common pathogenic mechanism in neurological and psychiatric disorders
2023, Brain, Behavior, and ImmunityCitation Excerpt :Following human herpes virus (HHV) 6A infection, HERV-W Env expression is induced through the transmembrane glycoprotein CD46, while no induction was observed upon exposure to HHV6B or the measles virus vaccine strain (Charvet et al., 2018). On the other hand, both subtypes HHV6A and HHV6B were found to activate HERV-K18 in B cells and PBMCs, respectively (Tai et al., 2009; Turcanova et al., 2009). In this context, a recent publication discusses accumulating evidence supporting the view that EBV, HHV6 and HERV-W can influence each other, eventually leading to dysregulation of the immune response (summarized in (Meier et al., 2021)).
Revisiting the antiviral theory to explain interferon-beta's effectiveness for relapsing multiple sclerosis
2022, Multiple Sclerosis and Related DisordersThe role of human endogenous retroviruses (HERVs) in Multiple Sclerosis and the plausible interplay between HERVs, Epstein–Barr virus infection, and vitamin D
2022, Multiple Sclerosis and Related DisordersCitation Excerpt :Given the SAg activity of the HERV-K18 env gene, EBV can transactivate the HERV-K18 SAg through a latent membrane protein (LMP)−2A, LMP-1, and its cellular receptor, CD21 (Sutkowski, 2004; Hsiao, 2006). It has been also shown that Human herpesvirus 6 (HHV-6)-A transactivates HERV-K18 directly, by the HHV-6A-infected cells, either in latent form or during acute infection (Tai, 2009) (Fig. 2). Moreover, with regards to the potential link between vitamin D and HERVs in MS, one study has reported an inverse correlation between MSRV DNA copy number and vitamin D concentration in RRMS patients, but not in healthy controls (Mostafa, 2017).
Herpesviruses and the hidden links to Multiple Sclerosis neuropathology
2021, Journal of NeuroimmunologyActivation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3
2021, Cell Stem CellCitation Excerpt :Thus, future studies will be needed to provide more detailed insights into epigenetic restriction factors contributing to HERV repression across different neural cell types. Although HERVs are typically repressed, they can be reactivated by environmental conditions, including radiation, chemicals, infectious agents (Dolei, 2018; Frank et al., 2006; Hohenadl et al., 1999; Küry et al., 2018), or exogenous viruses (Ruprecht et al., 2006; Tai et al., 2009; Vincendeau et al., 2015). An alternated chromatin state can result in de-silencing and activation of retrotransposons during normal aging (Benayoun et al., 2019; De Cecco et al., 2019; Simon et al., 2019).
Human endogenous retroviruses role in cancer cell stemness
2018, Seminars in Cancer Biology