Table 1 Studies with statistically significant correlation between MS and HHV-6 infection detected with serological, molecular and genotyping techniques
From: Human herpesvirus 6 infection as a trigger of multiple sclerosis: an update of recent literature
Study | Method | MS population | Additional Results | Moore and Wolfson | Canadian Task Force |
|---|---|---|---|---|---|
Bistrom et. al (2021) [17] | Serum IgG/IgM | 670 individuals who later developed relapsing MS and 670 matched controls HHV-6A seropositivity was associated with increased MS risk in all age groups | Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20–29 and 30–39 years | A | II-1 |
Perlejewski et al. (2020) [37] | CSF PCR | 4 MS patients and 13 controls Viral nucleic acid in seven (20.59%) MS patients and in one (7.69%) control patient | most frequently detected was human herpesvirus type 6 (HHV-6; 3 cases; 8.82%); | A | II-1 |
Amini et. al (2020) [18] | Serum IgG/IgM | 560 MS patients along with 560 healthy subjects were analyzed for HHV-6 seropositivity About 90.7% of MS patients (508/560) were seropositive for HHV-6, while 82.3% (461/560) of healthy subjects were seropositive for this virus (p = 0.001) | MMP-9 levels in seropositive MS patients were significantly higher than seronegative MS patients (p = 0.001). EDSS in seropositive MS patients was significantly higher in comparison to seronegative MS patients (p < 0.05) | A | II-1 |
Maria I Dominguez Mozo et. al (2020) [31] | Serum/CSF microRNA techniques | a significant correlation between the levels of serum hhv6b-miR-Ro6-2 and -3-5p, -2 and miR-U86 and -3-5p and miR-U86 also in the CSF, hhv6b-miR-Ro6-2 and -3-5p | 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 | A | II-1 |
Engdahl et al. (2019) [16] | Serum IgG/IgM | 8,742 MS and 478patients with preclinical forms The IgG response against IE1A was positively associated with increased risk of future MS | The IgG response against IE1B was negatively associated with MS | A | II-1 |
Ortega-Madueno et al. (2014) [7] | Serum IgG/IgM | 69% with a low HHV-6A/6B IgG titer after 2 years of DMTs free of relapse vs 40.7% with an increased titer (higher significance for Natalizumab) | HHV-6A IgG titers peak 1 week before relapse, HHV-6A/6B IgM titers peak 2 months after relapse | A | II-1 |
Simpson S. et al. (2012) [12] | Serum IgG/IgM | Dose dependent trend between rr and HHV6 IgG titer | Higher titers in female progressive MS patients rather than male | A | II-1 |
Khaki M. et al. (2011) [14] | Serum IgG/IgM | 61 patients and 60 controls screened for HHV6 amongst other viruses: OR = 2 [95%CI1-4], p = 0.04for HHV6 IgG | OR4.3[95%CI:2–9.3], p = 0.001 between MS patients and controls for HHV6 IgM | A | II-1 |
Behzad-Behbahani et al. (2011) [15] | Serum IgG/IgM Serum PCR | 30% serum samples with high HHV6 IgG titers and 33%withpositive HHV6 DNA. Significantly higher prevalence of HHV6 DNA in MS patientsvs controls, p = 0.001 | Higher HHV6 antibody and DNA titers in MS patients in relapse p = 0.001 | B | II-1 |
Ben-Fredj et al.(2013) [11] | Serum IgG/IgM, Serum PCR | 51.47% U94/REP HHV6 protein positive samples, 6.66% HHV6-DNA positive samples | Statistically significant results in both antibody and PCR techniques for relapses vs remission | A | II-1 |
Moghadam et al. (2015) [19] | Serum PCR | 28 out of 46 (60.8%) plasma samples of patients with MS were positive for viral DNA | The difference in prevalence of HHV-6 DNA in blood between patients with MS and controls was statistically significant OR 0.277 [95%CI: 0.12–0.89], p = 0.001 | A | II-1 |
Garcia-Montojo M. et al. (2011) [25] | Serum PCR | HHV6 DNA detected more frequently in MS patients with relapse. The rr was higher in patients with HHV6 DNA in serum, as well as the severity of the relapse | HHV6 DNA and clinical parameters could not be associated The response to IFN treatment (measured by rr reduction and severity of the relapse) was significantly less in MS patients with HHV6 DNA in serum | A | II-1 |
Nora-Krukle Z. et al. (2011) [20] | Serum PCR | 57%HHV6 DNA positive in RRMS patients 43% HHV6 DNA positive in SPMS patients | 66% patients without viremia were m-RNA HHV6 positive Significantly higher levels of IL-12 and TNF-a in MS patients with active infection vs patients with latent HHV6 infection | B | II-1 |
Dominguez-Mozo M et al. (2012) [24] | Genotyping, Serum PCR | Low levels of MHC2TA m-RNA levels at the initial visit and highlevelspostIFN treatment in patients with active HHV6 infection vs patients without | High MHC2TA m-RNA levels post IFN treatment 58.6% without active HHV6 infection responded to IFN treatment vs 23.8% of patients with active HHV6 infection | A | II-1 |
Blanco-Kelly et al. (2011) [28] | Genotyping, serum PCR | Polymorphisms TNFRSF6B and TNFRSF14 were associated with MS. The effects were stronger in patients with HHV6 active replication | TNFRSF6B-rs4809330OR 1.13 [95%CI: 0.82–1.53], p = 0.0008 TNFRSF14-rs6684865 OR1.2, p = 0.0008 [95%CI: 0.78–1.36] | A | II-1 |
Garcia-Montojo M. et al. (2011) [25] | Genotyping, Serum PCR | MHC2TA polymorphisms correlated with active replication (30.2%) Significant differences for MHC2TA between IFN-responders and non-responders | No significant results between the groups when active replication wasnot included | A | II-1 |
Vandenbroeck K. et al. (2011) [26] | Genotyping, Serum PCR | Association of polymorphism IRF5-rs3807306T and HHV6 infection OR 1.56 [95% Cl: 1.00–2.44], p = 0.05 | Response to IFN correlated with the same polymorphism (not statistically significant) OR 1.39 [95% Cl: 0.95–2.05], p = 0.09 | A | II-1 |
Alvarez-Lafuente R. et al. (2010) [27] | Genotyping,Serum PCR | Association of MHC2TA-rs4774C with HHV6 active replication | Allele C correlated with a different clinical response to treatment for MS patients 33% of MS patients without the allele responded to IFN, p = 0.05, 31% of MS patients without the allele had a better disease progression (EDSS = 1), p = 0.01 | A | II-1 |
Alenda R et al.(2014) [32] | CSF IgG/IgM | Presence of intrathecal HHV6 IgG antibodies in the CSF of MS patients | Major antigen is the major HHV6 capsid protein | A | II-1 |
Pietiläinen-Nicklén J et al. (2014) [33] | CSF IgG/IgM | Presence of HHV6 OCBs in MS patients | Earlier manifestation of the diseases in HHV6OCB patients | A | II-1 |
Virtanen JO et al. (2014) [35] | CSF IgG/IgM | 38% of the MS patients had OCBs related to HHV6 | HHV6 OCBs correlated with more GdE ( +) lesions | A | II-1 |
Virtanen JO et al. (2011) [36] | CSF IgG/IgM | 18% of OCB( +)ve patients were HHV6( +)ve,26%of the OCB( +)ve MS patients had HHV6 OCBs | HHV6( +)ve OCBs in other demyelinating diseases (21%) and other neurological diseases (10%) | A | II-1 |
Pietiläinen-Nicklén Jet al (2010) [34] | CSF IgG/IgM | Presence of OCBs in both acute and chronic MS | Association of the HHV6 infection with the symptoms of clinically possible MS | B | II-1 |