Abstract
The aberrant expression of human endogenous retrovirus (HERV) elements of the HERV-W family has been associated with different diseases, including multiple sclerosis (MS). In particular, the expression of the envelope protein (Env) from the multiple sclerosis-associated retrovirus (MSRV), a member of HERV-W family and known for its potent proinflammatory activity, is repeatedly detected in the brain lesions and blood of MS patients. Furthermore, human herpesvirus 6 (HHV-6) infection has long been suspected to play a role in the pathogenesis of MS and neuroinflammation. We show here that both HHV-6A and stimulation of its receptor, transmembrane glycoprotein CD46, induce the expression of MSRV-Env. The engagement of extracellular domains SCR3 and SCR4 of CD46-Cyt1 isoform was required for MSRV-env transactivation, limiting thus the MSRV-Env induction to the CD46 ligands binding these domains, including C3b component of complement, specific monoclonal antibodies, and both infectious and UV-inactivated HHV-6A, but neither HHV-6B nor measles virus vaccine strain. Induction of MSRV-Env required CD46 Cyt-1 singling and was abolished by the inhibitors of protein kinase C. Finally, both membrane-expressed and secreted MSRV-Env trigger TLR4 signaling, displaying thus a proinflammatory potential, characteristic for this viral protein. These data expand the specter of HHV-6A effects in the modulation of the immune response and support the hypothesis that cross-talks between exogenous and endogenous viruses may contribute to inflammatory diseases and participate in neuroinflammation. Furthermore, they reveal a new function of CD46, known as an inhibitor of complement activation and receptor for several pathogens, in transactivation of HERV env genes, which may play an important role in the pathogenesis of inflammatory diseases.
Highlights
Human endogenous retrovirus (HERV) sequences are assumed to be remnants of ancient retroviral infections of our ancestral germ-line cells and constitute ∼8% of the human genome [1]
We demonstrated the proinflammatory potential of human herpesvirus (HHV)-6A through the induction of MS-associated retrovirus (MSRV)-envelope protein (Env) which in turn activates TLR4 receptor. These results provide important information on the cross-talk between HHV-6A binding to its CD46 receptor and the transactivation of human endogenous retrovirus (HERV)-env genes leading to inflammation, which may play an important role in the pathogenesis of inflammatory diseases
To analyze the capacity of HHV-6A infection to transactivate MSRV-env gene, we examined initially the level of mRNA expression of MSRV-env in few cell types susceptible to HHV6A infection: T-cell line HSB-2, cord blood mononuclear cells and astroglyoblastoma cell line U87-MG (U87)
Summary
Human endogenous retrovirus (HERV) sequences are assumed to be remnants of ancient retroviral infections of our ancestral germ-line cells and constitute ∼8% of the human genome [1]. These viral sequences were generally silenced through diverse evolutionary mechanisms, some HERV genes have been shown to be expressed in controlled tissue-specific manner [2]. Two members of the HERV-W family have been studied with respect to MS: MS-associated retrovirus (MSRV), and the HERV-W fixed copy on chromosome7q Both are known to possess complete envelope protein ORF, MSRV-env and syncytin-1, respectively, sharing 93% of sequence identity. MSRV was associated with MS by numerous clinical studies [13, 14], the expression of HERVW env was increased in MS patients and correlated to poor prognosis [15]
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