Abstract
Human herpesvirus-6A (HHV-6A) and −6B (HHV-6B) might be involved in the etiopathogenesis of multiple sclerosis (MS), especially the HHV-6A. We aim at assessing, for the first time in the scientific literature, the HHV-6A/B microRNAs in MS patients. We analyzed the miRNAs of HHV-6A: miR-U86, and −6B: hhv6b-miR-Ro6-1, −2, −3-3p, −3-5p, and −4 in paired samples of serum and CSF of 42 untreated MS patients and 23 patients with other neurological diseases (OND), using Taqman MicroRNA Assays. Intrathecal HHV-6A/B antibody production and anti-HHV-6A/B IgG/IgM levels in serum were measured. MS clinical data were available. We detected the following miRNAs: hhv6b-miR-Ro6-2 (serum: MS:97.7%, OND:95.7%; CSF: MS:81%, OND:86.4%), 3-3p (serum: MS:4.8%, OND:0%; CSF: MS:2.4%, OND:4.5%), −3-5p (serum: MS:95.2%, OND:91.3%; CSF: MS:50%, OND:54.5%), and miR-U86 (serum: MS:54.8%, OND:47.8%; CSF: MS:11.9%, OND:9.1%). In the serum of the whole population (MS and OND patients) we found a significant correlation between the levels of hhv6b-miR-Ro6-2 and −3-5p (Spearman r = 0.839, pcorr = 3E-13), −2 and miR-U86 (Spearman r = 0.578, pcorr = 0.001) and −3-5p and miR-U86 (Spearman r = 0.698, pcorr = 1.34E-5); also in the CSF, between hhv6b-miR-Ro6-2 and −3-5p (Spearman r = 0.626, pcorr = 8.52E-4). These correlations remained statistically significant when both populations were considered separately. The anti-HHV-6A/B IgG levels in CSF and the intrathecal antibody production in positive MS patients for hhv6b-miR-Ro6-3-5p were statistically significant higher than in the negative ones (pcorr = 0.006 and pcorr = 0.036). The prevalence of miR-U86 (30.8%) in the CSF of individuals without gadolinium-enhancing lesions was higher (p = 0.035) than in the ones with these lesions (0%); however, the difference did not withstand Bonferroni correction (pcorr = 0.105). We propose a role of HHV-6A/B miRNAs in the maintenance of the viral latency state. Further investigations are warranted to validate these results and clarify the function of these viral miRNAs.
Highlights
Multiple sclerosis (MS) is a demyelinating inflammatory chronic disease that affects the central nervous system (CNS), and whose origin is probably autoimmune [1]
In the serum of the whole population (MS and other neurological diseases (OND) patients) we found a significant correlation between the levels of hhv6b-miR-Ro6-2 and −3-5p (Spearman r = 0.839, pcorr = 3E-13), −2 and miR-U86 (Spearman r = 0.578, pcorr = 0.001) and −3-5p and miR-U86 (Spearman r = 0.698, pcorr = 1.34E-5); in the cerebrospinal fluid (CSF), between hhv6b-miR-Ro6-2 and −3-5p (Spearman r = 0.626, pcorr = 8.52E-4)
We found a significant correlation between the levels of hhv6b-miR-Ro6-2, −3-5p, and miR-U86 in the whole population (MS and OND patients) (Figure 1), and in both populations independently (Table 3)
Summary
Multiple sclerosis (MS) is a demyelinating inflammatory chronic disease that affects the central nervous system (CNS), and whose origin is probably autoimmune [1]. Its genome is a linear doublestranded DNA molecule of 159–162 kb consisting of a long unique (U) region flanked by terminal direct repeats (left DRL and right DRR) of 8–9 kb Based on their temporal expression and their dependency on other gene products, its viral genes are divided into immediate-early (IE) genes, early (E) genes, and late (L) genes, like all herpesvirus [6]. HHV-6A/B has been classified as two distinct viruses, HHV-6A and HHV6B They share an overall identity of 90% out of their genome, but they differ in regards to their epidemiological, immunological, and biological properties, to their disease association [8]. This association remains controversial, since most of the studies did not distinguish between HHV-6A and −6B [11, 12]
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