Anti-Human Herpesvirus 6 A/B Antibodies Titers Correlate With Multiple Sclerosis-Associated Retrovirus Envelope Expression

Abstract

Human endogenous retrovirus W family envelope proteins (pHERV-W ENV/syncytin-1) have been repeatedly associated with multiple sclerosis (MS). Here, we have focused on the study of pHERV-W ENV/syncytin-1 expression levels in MS patients (relapsing and progressive forms) and in healthy donors (HD) and on exploring their possible relationship with Epstein-Barr virus (EBV) and human herpesvirus-6A/B (HHV-6A/B). We included blood samples from 101 MS patients and 37 HD to analyze antiviral antibody titers by ELISA and pHERV-W ENV/syncytin-1 expression levels by flow cytometry as well as by qPCR. Patients with relapsing MS forms showed significantly higher pHERV-W ENV/syncytin-1 protein and gene expression levels than HD. Progressive MS patients also showed significantly higher protein and gene expression levels than both HD and relapsing MS patients. Regarding antiviral antibodies titers, anti-HHV-6A/B IgM levels were positively correlated with pHERV-W ENV/syncytin-1 protein expression levels in patients with relapsing MS, while in the progressive forms patients this correlation was found with anti-HHVA/B IgG levels. Therefore, pHERV-W ENV could be involved in MS pathogenesis, playing a role in relapsing and progressive forms. Besides, anti-HHV-6A/B antibodies positively correlated with pHERV-W ENV expression. Further studies are needed to better understand this possible relationship.

Correlation between antibodies against the pathogenic pHERV‐W envelope protein and the inflammatory phase of multiple sclerosis

“…Our study reaffirms the connection between pHERV-W protein and disease severity, highlighting that even slight variations in amino acidic sequences between peptides can influence the immunological response. Consistent with our result, previous studies have reported higher gene expression levels of pHERV-W protein compared to syncytin-1 in patients with primary progressive and RRMS [26]. Moreover, elevated levels of extracellular RNA viral loads and HERV-Fc1 gag gene expression were detected in AMS patients compared to SMS and HCs [27].…”

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

“…By carrying stretches of telomeric repeats at their linear genome, the variants HHV-6A and HHV-6B are able to integrate into human chromosomes and become latent [ 160 ]. This virus has been found in several human diseases, including autoimmunity [ 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ], ME/CFS [ 190 , 191 , 192 , 193 ], mitochondrial dysfunction [ 193 , 194 ], and in patients with moderate to critical COVID-19 [ 42 , 43 , 44 , 195 , 196 ]. Among the autoimmune diseases associated with HHV-6, the most frequently cited is multiple sclerosis (MS) [ 170 , 171 , 172 , 173 , 174 , 175 , 176 , …”

“…This has been demonstrated by the direct detection of the HHV-6 genome and antigens in the blood and brain of patients with MS [ 176 , 177 , 178 , 181 , 182 , 183 ]. Furthermore, not only were higher levels of anti-HHV-6 A/B antibodies detected in the blood of MS patients, their titers also correlated with the severity of the disease [ 170 ] and in predicting risk of relapse [ 184 , 185 , 186 ]. Researchers further concluded that in addition to its potential etiologic role in MS, infection with HHV-6 or immune reaction against it may also have an effect on MS relapse and its progression [ 184 ].…”

“…Although it is already very well-known how viruses, including HHV-6, through molecular mimicry, bystander activation, epitope spreading, and activation of autoreactive Th1 and Th17 cells induce various autoimmune diseases [ 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 ], the breakdown of thymic central tolerance by viruses such as HHV-6 and HHV-7 is a novel one.…”

Epstein-Barr Virus Load Correlates with Multiple Sclerosis-Associated Retrovirus Envelope Expression

“…cDNA was synthesized from RNA using the Transcriptor First Strand cDNA Synthesis kit (Roche Diagnostics, S.L., Barcelona, Spain), where negative controls (without retrotranscriptase) were included. For pHERV-W ENV and syncytin-1 gene expression quantification, we followed our previously published protocol [ 17 ].…”