Vitamin D and Viruses that can trigger Me/CFS

percyval577

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EBV, CMV and one Enterovirus have been found to act on the vitamin D recpetor VDR.
HCV is associated with vitamin D, Parvovirus can be associated.
HHV-6 comes up with only one (negative) finding in respect of vitamin D, but can be associated.
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Epstein-Barr virus encoded EBNA-3 binds to vitamin D receptor and blocks activation of its target genes.
Yenamandra et al 2010


Abstract (my paragraphing)
Epstein-Barr virus (EBV) is a human gamma herpes virus that infects B cells and induces their transformation into immortalized lymphoblasts that can grow as cell lines (LCLs) in vitro. EBNA-3 is a member of the EBNA-3-protein family that can regulate transcription of cellular and viral genes.

The identification of EBNA-3 cellular partners and a study of its influence on cellular pathways are important for understanding the transforming action of the virus.

In this work, we have identified the vitamin D receptor (VDR) protein as a binding partner of EBNA-3. We found that EBNA3 blocks the activation of VDR-dependent genes and

protects LCLs against vitamin-D3-induced growth arrest and/or apoptosis. The presented data shed some light on the anti-apoptotic EBV program and the role of the EBNA-3-VDR interaction in the viral strategy.
paywalled
Cell Mol Life Sci. 2010 Dec;67(24):4249-56. doi: 10.1007/s00018-010-0441-4. Epub 2010 Jul 1.
 
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percyval577

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Human cytomegalovirus infection downregulates vitamin-D receptor in mammalian cells.
Rieder et al 2017


Abstract (my paragraphing)
Vitamin D (VD) is essential for the human body and involved in a wide variety of critical physiological processes including bone, muscle, and cardiovascular health, as well as innate immunity and antimicrobial responses. Here, we elucidated the significance of the VD system in cytomegalovirus (CMV) infection, which is one of the most common opportunistic infections in immunocompromised or -suppressed patients.

We found that expression of vitamin D receptor (VDR) was downregulated in CMV-infected cells within 12h [hrs] post infection [p.i.] to 12% relative to VDR expression in mock-infected fibroblasts and did not recover during the CMV replication cycle of 96h.

None of the biologically active metabolites of VD, cholecalciferol, calcidiol, or calcitriol, inhibit CMV replication significantly in human fibroblasts. In a feedback loop, expression of CYP24A1 dropped to 3% by 12h p.i. and expression of CYP27B1 increased gradually during the replication cycle of CMV to 970% probably as a consequence of VDR inhibition.

VDR expression was not downregulated during influenza virus or adenovirus replication. The potent synthetic vitamin D analog EB-1089 was not able to inhibit CMV replication or antagonize its effect on VDR expression. Only CMV replication, and none of the other viral pathogens evaluated, inhibited the vitamin D system in vitro.

In view of the pleiotropism of VDR, CMV-mediated downregulation may have far-reaching virological, immunological, and clinical implications and thus warrant further evaluations in vitro and in vivo.
open acces
J Steroid Biochem Mol Biol. 2017 Jan;165(Pt B):356-362. doi: 10.1016/j.jsbmb.2016.08.002. Epub 2016 Aug 9.
 

percyval577

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an enterovirus:

Vitamin D receptor protects glioblastoma A172 cells against Coxsackievirus A16 infection induced cell death in the pathogenesis of hand, foot, and mouth disease.
Qu et al 2017


Abstract (my pragraphing)
Hand, foot, and mouth disease (HFMD) was one of the most common children illnesses. Coxsackievirus A16 was one of the major pathogens that cause HFMD.

However, the role of vitamin D underlying this common illness has not been elucidated. Our study examined that vitamin D levels was significantly lower in 33 HFMD patients, compared to 36 healthy children.

Unexpectedly, both mRNA and protein expression of VDR were significantly decreased in CA16 infected glioblastoma A172 cells. And overexpression of VDR or vitamin D treatment in CA16 infected glioblastoma A172 cells could reverse the CA16 infection induced cell death, apoptosis or mitochondrial membrane rupture.

Therefore, our study, for the first time, demonstrated that vitamin D and VDR could associate with the pathogenesis of HFMD. Thus might provide useful information for HFMD prevention and treatments.
paywalled
Biochem Biophys Res Commun. 2017 Nov 18;493(2):952-956. doi: 10.1016/j.bbrc.2017.09.112. Epub 2017 Sep 21.
 
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percyval577

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this might be not too conclusive:

Association between vitamin D and hepatitis C virus infection: A meta-analysis.
Villar et al 2013


Abstract
AIM: To evaluate the association between 25-hydroxyvitamin D [25(OH)D] and sustained virological response (SVR) in hepatitis C virus (HCV) infected individuals.

METHODS: Relevant studies were identified by systematically searching MEDLINE databases up to March 2012 and abstracts of the European and American Congress of Hepatology conducted in 2011. Studies must provide information on SVR and the levels of 25(OH)D3 and/or 25(OH)D2 [henceforth referred to as 25(OH)D] in sera samples from HCV infected individuals. The inclusion criteria were: clinical studies that included HCV infected patients aged older than 18 years regardless of HCV genotype or ethnic group; provided information on SVR rates; and were reported in the English language as full papers. Due to the heterogeneity of studies in categorizing serum vitamin D levels, a cut-off value of 30 ng/mL of serum 25(OH)D was used. Heterogeneity was assessed using I2 statistics. The summary odds ratios with their corresponding 95%CI were calculated based on a random-effects model.

RESULTS: Overall, 11 studies (8 observational and 3 interventional) involving 1575 individuals were included and 1117 HCV infected individuals (71%) showed low vitamin D levels. Most of the studies included mono-infected HCV individuals with the mean age ranging from 38 to 56 years. Four studies were conducted in human immunodeficiency virus/HCV infected individuals. Regarding vitamin D measurement, most of the studies employed radioimmunoassays (n = 5) followed by chemiluminescence (n= 4) and just one study employed high performance/pressure liquid chromatography (HPLC). Basal vitamin D levels varied from 17 to 43 ng/mL in the studies selected, and most of the HCV infected individuals had genotype 1 (1068/1575) with mean viral load varying from log 4.5-5.9 UI/mL. With regard to HCV treatment, most of the studies (n = 8) included HCV individuals without previous treatment, where the pooled SVR rate was 46.4%. High rates of SVR were observed in HCV individuals with vitamin D levels above 30 ng/mL (OR = 1.57; 95%CI: 1.12-2.2) and those supplemented with vitamin D (OR = 4.59; 95%CI: 1.67-12.63) regardless of genotype.

CONCLUSION: Our results demonstrated high prevalence of vitamin D deficiency and high SVR in individuals with higher serum vitamin D levels or receiving vitamin D supplementation.
open acces
World J Gastroenterol. 2013 Sep 21; 19(35): 5917–5924. Published online 2013 Sep 21. doi: 10.3748/wjg.v19.i35.5917
 
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percyval577

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speculative linkage with two reviews:

The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmunedisease.
Jonathan Kerr 2015


Abstract (my paragraphing)
Human parvovirus B19 is a single-stranded DNA virus which preferentially targets the erythroblasts in the bone marrow. B19 infection commonly causes erythema infectiosum, arthralgia, fetal death, transient aplastic crisis in patients with shortened red cell survival, and persistent infection in people who are immunocompromised.

Less common clinical manifestations include atypical skin rashes, neurological syndromes, cardiac syndromes, and various cytopenias. B19 infection has also been associated with development of a variety of different autoimmune diseases, including rheumatological, neurological, neuromuscular, cardiovascular, haematological, nephrological and metabolic.

Production of a variety of autoantibodies has been demonstrated to occur during B19 infection and these have been shown to be key to the pathogenesis of the particular disease process in a significant number of cases, for example, production of rheumatoid factor in cases of B19-associated rheumatoid arthritis and production of anti-glutamic acid decarboxylase (GAD) in patients with B19-associated type 1 diabetes mellitus.

B19 infection has also been associated with the development of multiple autoimmune diseases in 12 individuals. Documented mechanisms in B19-associated autoimmunity include molecular mimicry (IgG antibody to B19 proteins has been shown to cross react with a variety of recognised human autoantigens, including collagen II, keratin, angiotensin II type 1 receptor, myelin basic protein, cardiolipin, and platelet membrane glycoprotein IIb/IIIa), B19-induced apoptosis with presentation of self-antigens to T lymphocytes, and the phospholipase activity of the B19 unique VP1 protein.
open acces
J Clin Pathol. 2016 Apr;69(4):279-91. doi: 10.1136/jclinpath-2015-203455. Epub 2015 Dec 7.

note that Jonathan Kerr in his recent article on ME/CFS judged that it would be an "autoimmune-like disease"


Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential.
Dankers et al 2017


Abstract (my paragraphing)
Over the last three decades, it has become clear that the role of vitamin D goes beyond the regulation of calcium homeostasis and bone health. An important extraskeletal effect of vitamin D is the modulation of the immune system.

In the context of autoimmune diseases, this is illustrated by correlations of vitamin D status and genetic polymorphisms in the vitamin D receptor with the incidence and severity of the disease. These correlations warrant investigation into the potential use of vitamin D in the treatment of patients with autoimmune diseases. In recent years, several clinical trials have been performed to investigate the therapeutic value of vitamin D in multiple sclerosis, rheumatoid arthritis, Crohn's disease, type I diabetes, and systemic lupus erythematosus.

Additionally, a second angle of investigation has focused on unraveling the molecular pathways used by vitamin D in order to find new potential therapeutic targets. This review will not only provide an overview of the clinical trials that have been performed but also discuss the current knowledge about the molecular mechanisms underlying the immunomodulatory effects of vitamin D and how these advances can be used in the treatment of autoimmune diseases.
open acces
Front Immunol. 2017 Jan 20;7:697. doi: 10.3389/fimmu.2016.00697. eCollection 2016.
 
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percyval577

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for HVV-6 google told only one negative finding:

Vitamin D serum levels and viral load of human herpesvirus and Epstein-Barr virus in patients with multiple sclerosis after one year of follow up.
Alvarez-Lafuente 2017


Abstract
Background: Low levels of 25-hydroxyvitamin D (25-(OH)D2) have been described as one of the possible environmental factors involved in multiple sclerosis (MS) etiopathogenesis. In addition, Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) infection have also been proposed as MS triggers. A possible effect of vitamin D levels on viral status have been suggested.

Objectives: To analyse the replication/reactivation of EBV and HHV-6 in MS patients regarding the serum levels of 25-(OH)D2, in order to investigate the possible relationship between vitamin D levels and viral status.

Methods: 200 MS patients were included in this retrospective longitudinal study of one year follow-up. For each one of the patients, two peripheral blood and serum samples were collected, in such a way that data were obtained from both semesters of the year. DNA was extracted from blood in order to analyse EBV and HHV-6 viral load in peripheral blood cells by quantitative real-time PCR. 25-(OH)D2 was determined using a delayed one step chemiluminiscent microparticle immunoassay (Abbott) from serum samples.

Results: The median value for 25-(OH)D2 in the first semester of the year among the MS patients included in the study was 17.5 ng/ml (ranging between 15.5 ng/ml in March and 19.3 ng/ml in June); the median value for 25-(OH)D2 in the second semester of the year was 24.6 ng/ml (ranging between 19.6 ng/ml in December and 28.4 ng/ml in September). In the first semester of the year, 22% of MS patients were positive by qPCR for EBV when 25-(OH)D2< 11 ng/ml, and only just 4% were positive when 25-(OH)D2>20 ng/ml (p=0.03). In addition, EBV viral load was higher in those MS patients with lower 25-(OH)D2 levels, compared to those with levels above 20 ng/ml (p=0.04).
For HHV-6, there were no differences between MS patients with high and low 25-(OH)D2 levels. Moreover, no differences were found in the second semester of the year, neither for EBV nor HHV-6, when 25-(OH)D2 levels were higher and only 28.4% of the samples had levels < 20 ng/ml in comparison with the 64.3% in the first semester of the year.

Conclusions: Vitamin D levels could be involved in the regulation of the replication/reactivation of EBV in peripheral blood cells of MS patients; moreover, viral load seems to be higher when 25-(OH)D2 levels in serum are low. Further studies, also in healthy controls, are required.
paywalled.
 

percyval577

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via telomeres there can be made an association between HHV-6 and vitamin D:

HHV-6A/B Integration and the Pathogenesis Associated with the Reactivation of Chromosomically Integrated HHV-6A
Collin and Flammand 2017


5.2
For most herpesviruses, integration into host chromosomes is an unusual event. In some cases, it was observed that in the presence of DNA breaks induced by UV radiation, human herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) can integrate into chromosomes. However, the integrated HSV-1 and HSV-2 genome were fragmented and mutated, not able to generate new virions [72]. In contrast to HSV-1 and HSV-2, HHV-6A/B integrated genomes remain largely intact with their ORFs conserved.
7. Conclusions
Though reported 25 years ago, the study of HHV-6A/B integration remains understudied. With the development of HHV-6A/B integration systems [86] and genome editing technologies, scientists should be able to tease out in detail the mechanisms leading to viral integration. Considering a prevalence of approximately 1%, pinpointing the association between iciHHV-6A/B and diseases is not trivial. This will require considerable effort, funding and access to large biobanks linked to detailed medical records. Scientists will likely need to share and pool their data to reach meaningful conclusions, especially for less-prevalent diseases. Furthermore, considering that appearance of a disease is likely to be influenced by the chromosome carrying the integrated HHV-6A/B as well of the sex of the individual, these variables should be taken into consideration during data analyses.
open acces
Viruses. 2017 Jun 26;9(7). pii: E160. doi: 10.3390/v9070160.



The role of telomeres and vitamin D in cellular aging and age-related disease
Pusceddu et al 2015


Studies in humans, page 1671, my paragraphing
A summary of the literature data regarding the link between telomere biology and vitamin D is reported in Table 1.

Richards et al. were the first to demonstrate a positive correlation between serum 25-OHD and LTL in humans, which remained significant after adjustment for age [139]. In their study they analyzed 2160 women of the TwinsUK cohort. After multiple adjustments for age, season of vitamin D measurement, menopausal status, use of hormone replacement therapy and physical activity, the difference in telomere length between the highest (124±37.3 nmol/L) and lowest (40.9±11 nmol/L) tertile of 25-OHD concentrations was equivalent to 5 years of telomeric aging [139]. In addition, the authors analyzed a subpopulation of 700 women that used vitamin D supplements. On average, these women had longer telomeres than women who did not use vitamin D supplements. However this difference was not statistically significant.

These initial findings were confirmed by a subsequent study performed by Liu et al. [143]. In this study, analyses were performed on 1424 women of the Nurses’ Health Study and the results showed a positive correlation between LTL and serum 25-OHD concentrations. Logistic regression analysis indicated a concentration-dependent relationship. However, calcium intake modified this association significantly. 1,25(OH)2 D was also measured, but did not correlate with LTL.

As single nucleotide polymorphisms (SNPs) in genes involved in vitamin D metabolism (like SNPs in VDR, VDBP CYP2R1 and DHCR7), are reported to affect vitamin D blood concentrations, Liu et al. analyzed vitamin D-related SNPs in their population. They identified a positive association between rs7041 and rs4588 (both SNPs of VDBP), and 25-OHD levels. However, none of the investigated vitamin D-related SNPs were significantly associated with LTL [143].

Beside these cross-sectional studies, only one interventional study has been performed in order to clarify the effect of vitamin D supplementation on telomere biology [141]. Zhu et al. treated 37 obese Afro-American subjects in a double-blind randomized fashion with either a monthly oral dose of 60,000 IU of vitamin D3 or placebo for a period of 4 months. At the end of the study the serum 25-OHD concentration in vitamin D treated subjects was markedly increased when compared to baseline. The rise in serum 25-OHD was accompanied by a 19.2% increase of peripheral blood mononuclear cell (PBMC) telomerase activity. In the placebo group no such changes were seen. However, LTL was not measured in this study, limiting also the power of their findings. Further support for vitamin supplementation preserving telomere length comes from a recent study in hemodialysis patients [140].

Borras et al. observed longer telomeres in hemodialysis patients treated with calcitriol or analogs for at least 6 months compared to hemodialysis patients without such treatment [140].

Finally, Hoffecker et al. reported a significant correlation between telomere length and serum 25-OHD concentrations in vitamin D deficient (serum 25-OHD  < 20 ng/mL) patients with systemic lupus erythematosus (SLE) and unaffected controls [142]. Moreover, patients with SLE whose serum 25-OHD concentrations remained insufficient/deficient ( < 30 ng/mL) after 2.8 years of follow-up had shorter telomeres than patients with a sufficient serum 25-OHD concentration ( > 30 ng/mL).
open acces
Clinical Chemistry and Laboratory Medicine 21.03.2015 | DOI: https://doi.org/10.1515/cclm-2014-1184

thread on telomeres
 

Sidny

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So if we can cure or eradicate these viruses from our bodies would that concievably restore vitamin D receptor function?
 

uglevod

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Sidny

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How it is possible to eradicate those viruses they are all intercellular...
Gene editing is showing promise in that regard. Technologies like DRACO and viralym-m seem like functional cures also.

Kieth Jerome at Fred hutch research center is working on endonucleases that apparently have been able to delete up to 90% of HSV in mouse ganglia. I think they’ve shown crispr as being effective for EBV already.
 

Sidny

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This still does not prove that raising the levels of Vit D via sun/supplements will magically low EBV load. Separate in-vivo study is required.
Agreed. If various viruses such as EBV are down regulating and interfering with vitamin D receptor function I’m not sure how simply supplemeting with it will make much of a difference.

In that sense I think lowering EBV load through antivirals or other means might actually work better to raise vitamin D.

The links @percyval577 posted seem to indicate it’s not so much about what vitamin d levels are but how these pathogens prevent the body from utilizing it appropriately.

The Marshall protocol seems to take much of this into consideration although I think avoiding vitamin d all together can be problematic in its own right.