Cumulative Roles for Epstein-Barr Virus, Human Endogenous Retroviruses, and Human Herpes Virus-6 in Driving an Inflammatory Cascade Underlying MS Pathogenesis

Abstract

Roles for viral infections and aberrant immune responses in driving localized neuroinflammation and neurodegeneration in multiple sclerosis (MS) are the focus of intense research. Epstein-Barr virus (EBV), as a persistent and frequently reactivating virus with major immunogenic influences and a near 100% epidemiological association with MS, is considered to play a leading role in MS pathogenesis, triggering localized inflammation near or within the central nervous system (CNS). This triggering may occur directly via viral products (RNA and protein) and/or indirectly via antigenic mimicry involving B-cells, T-cells and cytokine-activated astrocytes and microglia cells damaging the myelin sheath of neurons. The genetic MS-risk factor HLA-DR2b (DRB1*1501β, DRA1*0101α) may contribute to aberrant EBV antigen-presentation and anti-EBV reactivity but also to mimicry-induced autoimmune responses characteristic of MS. A central role is proposed for inflammatory EBER1, EBV-miRNA and LMP1 containing exosomes secreted by viable reactivating EBV+ B-cells and repetitive release of EBNA1-DNA complexes from apoptotic EBV+ B-cells, forming reactive immune complexes with EBNA1-IgG and complement. This may be accompanied by cytokine- or EBV-induced expression of human endogenous retrovirus-W/-K (HERV-W/-K) elements and possibly by activation of human herpesvirus-6A (HHV-6A) in early-stage CNS lesions, each contributing to an inflammatory cascade causing the relapsing-remitting neuro-inflammatory and/or progressive features characteristic of MS. Elimination of EBV-carrying B-cells by antibody- and EBV-specific T-cell therapy may hold the promise of reducing EBV activity in the CNS, thereby limiting CNS inflammation, MS symptoms and possibly reversing disease. Other approaches targeting HHV-6 and HERV-W and limiting inflammatory kinase-signaling to treat MS are also being tested with promising results. This article presents an overview of the evidence that EBV, HHV-6, and HERV-W may have a pathogenic role in initiating and promoting MS and possible approaches to mitigate development of the disease.

Chromosome breaks in breast cancers occur near herpes tumor virus sequences and explain why the cancer comes back

“…Retroviral sequences constitute 8% of the human genome. EBV can trans-activate endogenous retroviruses (Bruce et al , 2021; Mameli et al , 2012; Meier et al , 2021), In the present work, I did not address how retroviruses impact breast cancer risk, but they may make a significant contribution.…”

“…Aberrant methylation in breast cancer occurs at hundreds of host gene promoters and distal sequences (Batra et al 2021). EBV can also trans-activate endogenous retroviruses (Bruce et al 2021;Mameli et al 2012;Meier et al 2021), In B-lymphocytes, EBV causes chromosome structural changes that foster breakage fusion-bridge-cycles and characteristic chromosome rearrangements. These structural changes include forming chromosomes with two centromeres (dicentric chromosomes), chromosomal deletions, fragmentation, unbalanced translocations, and telomere dysfunction (Kamranvar et al 2007;Lacoste et al 2010).…”

High Prevalence of Common Human Viruses in Thyroid Tissue

“…It remains an open question whether carrying two or more viruses in the thyroid confers an increasing risk for AITD. It may be of interest to recall that HHV-6 transactivates EBV ( 68 ) and that the risk for multiple sclerosis increases when genetically predisposed persons become doubly infected with HHV-6A and EBV ( 69 ). Interestingly, a recent study shows that neonatal infection of mice with a roseolovirus related to HHV-6 may damage the thymus, thus disrupting central tolerance and causing autoimmunity later in life ( 70 ).…”

Human Herpesvirus 6A Is a Risk Factor for Multiple Sclerosis

“…Human herpesvirus (HHV)-6A joins a group of herpesviruses suspected of modulating MS susceptibility and progression, most notably Epstein Barr Virus (EBV) and Cytomegalovirus (CMV) ( 9 ). HHV-6 ( 10 ) belongs to the β-herpesvirus subfamily of Herpesviridae that can establish lifelong latent infections in the host.…”