Both infectious and UV-inactivated HHV-6A activate endogenous retrovirus envelope protein – but so does selective stimulation of HHV-6A’s CD46 receptor. This “cross-talk” between HHV-6A and endogenous retrovirus appears to play an important role in the pathogenesis of inflammatory diseases.
A team in France led by Dr. Branka Horvat at the International Center for Infectiology Research (CIRI) in Lyon, in collaboration with Dr. Patrice Marche (INSERM, Grenoble) and Dr. Herve Perron (GeNeuro Inovation, Lyon) demonstrated that HHV-6A as well as stimulation of transmembrane glycoprotein CD46 induced the expression of an envelope protein of MSRV or multiple sclerosis associated retrovirus, a member of the human endogenous retrovirus (HERV-W) family. Specifically, they found that engagement of extracellular domains SCR3 and SCR4 of the CD46-Cyt1 isoform is required for the transactivation. In addition, they found that specific monoclonal antibodies and the C3b component of complement also caused transactivation.
Neither HHV-6B HST strain nor measles virus (which also utilizes the CD46 receptor) had any impact the expression of the endogenous retrovirus proteins. The group also demonstrated that the MRSV envelope protein generates inflammation by triggering T toll receptor 4 signaling.
Of interest, they were able to block the induction of the MSRV envelope protein using inhibitors of protein kinase C which block the required Cyt-1 signaling. Cyt-1 is one of two CD46 cytoplasmic isoform groups.
A previous study from Per Höllsberg's laboratory at University of Aarhus found that one strain of HHV6B, the PL strain which requires CD46 Cyt-1 for infection, induced the expression of HERV-K18 mRNA (Turcanova 2009).
Endogenous retrovirus sequences comprise approximately 8% of the human genome and are assumed to be remnants of ancient retrovirus infections, and are thought to be involved in multiple sclerosis (MS), type 1 diabetes schizophrenia and bipolar disorder, as well as several degenerative diseases.
Aberrant expression of human endogenous retrovirus, especially the envelope protein from the MSRV has potent pro-inflammatory effects and is often detected in brain lesions and blood of MS patients.
Both Epstein-Barr virus (EBV) and herpes simplex virus 1 (HSV-1) have previously been shown to activate HERV env genes in vitro (Küry 2018) and both HHV-6A and HHV-6B activated transcription of HERV-K18 (Turcanova 2009). Both EBV and HHV-6 have been positively associated with MS disease progression.
Previous studies have shown that EBV transactivates HERV K18 before the transcription of viral genes by docking to the human complement receptor CD21 (Hsiao 2006) and a group headed by Per Hollsberg showed the PL strain of HHV-6B (that requires CD46 Cyt1 for infection) induced expression of HERV-K18 mRNA without the requirement for viral transcription and replication (Turcanova 2009).
HHV-6A has long been suspected of playing a role in multiple sclerosis. MSRV has been associated with MS in several clinical studies (Dolei 2002) and that the expression of HERV-W envelope protein (ENV) is increased in MS and correlates to poor prognosis (Sotgiu 2006).
The French group notes that CD46-induced activation of MSRV-env transactivation may be triggered by other pathogens using CD46 as a receptor, such as the pathogenic bacteria Streptococci, as that it could also be triggered by other conditions where the production of the C3b component of complement is produced, suggesting a multifactorial etiology of various human diseases including MS.
They also note that the CD46 pathway may be dysfunctional in certain patients, contributing to chronic inflammatory diseases and state that further understanding of the role of CD46 in the induction of HERV-ENV may provide important insight for developing preventative and therapeutic anti-inflammatory interventions.
Read the full study: Charvet 2018
The Horvat lab is pictured below. Branka Horvat, is at the far right.