Vitamin B12 and hepatitis C: molecular biology and human pathology. (original) (raw)
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Vitamin B12 stalls the 80 S ribosomal complex on the hepatitis C internal ribosome entry site.
The effect of cyanocobalamin (CNCbl, vitamin B12) on hepatitis C virus internal ribosome entry site (HCV IRES)-dependent initiation of translation was studied by ribosomal toeprinting and sucrose gradient centrifugation analysis. These results suggested that CNCbl did not inhibit HCV IRES-dependent translation by a competitive binding mechanism. CNCbl allowed 80 S elongation complex formation on the mRNA, but stalled the initiation at that point, effectively trapping the 80 S ribosomal complexes on the HCV IRES. CNCbl had no effect on cap-dependent mRNA, consistent with the known mRNA specificity of this translational inhibitor. To help elucidate the mechanism, comparative data were collected for the well-characterised translation inhibitors cycloheximide and 5'-guanylyl-imidophosphate. Although CNCbl stalled HCV IRES-dependent translation at approximately the same step in initiation as cycloheximide, the mechanisms of these two inhibitors are distinct.
To investigate the role of the hepatitis C virus internal ribosome entry site (HCV IRES) domain IV in translation initiation and regulation, two chimeric IRES elements were constructed to contain the reciprocal domain IV in the otherwise HCV and classical swine fever virus IRES elements. This permitted an examination of the role of domain IV in the control of HCV translation. A specific inhibitor of the HCV IRES, vitamin B(12), was shown to inhibit translation directed by all IRES elements which contained domain IV from the HCV and the GB virus B IRES elements, whereas the HCV core protein could only suppress translation from the wild-type HCV IRES. Thus, the mechanisms of translation inhibition by vitamin B(12) and the core protein differ, and they target different regions of the IRES.
Gut, 2013
In vitro, vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication. To assess the effect of vitamin B12 on virological response in patients with chronic HCV hepatitis naïve to antiviral therapy. Ninety-four patients with chronic HCV hepatitis were randomly assigned to receive pegylated interferon α plus ribavirin (standard-of-care; SOC) or SOC plus vitamin B12 (SOC+B12). Viral response-namely, undetectable serum HCV-RNA, was evaluated 4 weeks after starting treatment (rapid viral response), 12 weeks after starting treatment (complete early viral response) and 24 or 48 weeks after starting treatment (end-of-treatment viral response) and 24 weeks after completing treatment (sustained viral response (SVR)). Genotyping for the interleukin (IL)-28B polymorphism was performed a posteriori in a subset (42/64) of HCV genotype 1 carriers. Overall, rapid viral response did not differ between the two groups, whereas the rates of complete early viral response (p=0.03), end-of-treatment viral response (p=0.03) and SVR (p=0.001) were significantly higher in SOC+B12 patients than in SOC patients. In SOC+B12 patients, the SVR rate was also significantly higher in carriers of a difficult-to-treat genotype (p=0.002) and in patients with a high baseline viral load (p=0.002). Distribution of genotype IL-28B did not differ between the two groups. At multivariate analysis, only easy-to-treat HCV genotypes (OR=9.00; 95% CI 2.5 to 37.5; p=0.001) and vitamin B12 supplementation (OR=6.9; 95% CI 2.0 to 23.6; p=0.002) were independently associated with SVR. Vitamin B12 supplementation significantly improves SVR rates in HCV-infected patients naïve to antiviral therapy.
Biomedical Research and Therapy
Introduction: Hepatitis C virus (HCV) infection affects almost 180 million people around the world. Even though the development of direct acting antivirals (DAAs) has significantly improved the treatment responses to HCV infection, treatment with pegylated interferon (PegIFN) in combination with ribavirin is considered the standard of care (SOC) for chronic HCV infection treatment in countries with limited medical resources. Considering the inhibitory effect of vitamin B12 on HCV replication, we have evaluated the effect of vitamin B12 supplementation along with SOC on treatment outcomes in patients with chronic HCV infection, who were antiviral treatment-naive. Methods: In this regard, seventy-four HCV-infected patients, naïve to antiviral therapy, were randomly assigned to receive SOC or SOC in addition to vitamin B12 (SOC + B12). Viral response was evaluated at 4, 12, 24 and 48 weeks following the initiation of viral treatment and at 24 weeks after completing the treatment. Genot...
Letters in Applied NanoBioScience
Several studies have revealed an association between the high serum levels of vitamin B12 (vit B12) and the stage of chronic liver diseases. This study analyzes serum vit B12 levels among Egyptian hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) patients. The serum levels of vit B12 were examined in HCV patients without cirrhosis (HCV group, n=30), with cirrhosis (HCV+cirrhosis group, n=24), HCC patients (HCC group, n=30), and healthy individuals (control group, n=16). Serum vit B12 levels increased significantly in HCV+cirrhosis and HCC groups compared with the control group. HCC patients showed a significant increase in vit B12 levels compared with HCV patients with cirrhosis. Moreover, HCV patients without cirrhosis showed no significant increase in vit B12 level than the control group. Also, patients with fibrosis scores (F) from F2 to F4 showed a significant increase in serum vit B12 levels compared with the control group. Regarding correlations with liver functions, ...
Vitamin D: An innate antiviral agent suppressing hepatitis C virus in human hepatocytes
Hepatology, 2011
Vitamin D supplementation was reported to improve the probability of achieving a sustained virological response when combined with antiviral treatment against hepatitis C virus (HCV). Our aim was to determine the in vitro potential of vitamin D to inhibit HCV infectious virus production and explore the mechanism(s) of inhibition. Here we show that vitamin D 3 remarkably inhibits HCV production in Huh7.5 hepatoma cells. These cells express CYP27B1, the gene encoding for the enzyme responsible for the synthesis of the vitamin D hormonally active metabolite, calcitriol. Treatment with vitamin D 3 resulted in calcitriol production and induction of calcitriol target gene CYP24A1, indicating that these cells contain the full machinery for vitamin D metabolism and activity. Notably, treatment with calcitriol resulted in HCV inhibition. Collectively, these findings suggest that vitamin D 3 has an antiviral activity which is mediated by its active metabolite. This antiviral activity involves the induction of the interferon signaling pathway, resulting in expression of interferon-b and the interferon-stimulated gene, MxA. Intriguingly, HCV infection increased calcitriol production by inhibiting CYP24A1 induction, the enzyme responsible for the first step in calcitriol catabolism. Importantly, the combination of vitamin D 3 or calcitriol and interferon-a synergistically inhibited viral production. Conclusion: This study demonstrates for the first time a direct antiviral effect of vitamin D in an in vitro infectious virus production system. It proposes an interplay between the hepatic vitamin D endocrine system and HCV, suggesting that vitamin D has a role as a natural antiviral mediator. Importantly, our study implies that vitamin D might have an interferon-sparing effect, thus improving antiviral treatment of HCV-infected patients. (HEPATOLOGY 2011;54:1570-1579 Abbreviations: 1a-hydroxylase, 25-hydroxyvitamin-D 1a-hydroxylase; 1a,25(OH)2D, 1a,25-dihydroxyvitamin D; 24-hydroxylase, 25-hydroxyvitamin-D 24hydroxylase; 25(OH)D, 25-hydroxyvitamin D
Vitamins in the treatment of chronic viral hepatitis
British Journal of Nutrition, 2011
Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic infections represent a major health problem worldwide. Although the efficacy of HBV and HCV treatment has improved, several important problems remain. Current recommended antiviral treatments are associated with considerable expense, adverse effects and poor efficacy in some patients. Thus, several alternative approaches have been attempted. To review the clinical experiences investigating the use of lipid- and water-soluble vitamins in the treatment of HBV- and HCV-related chronic infections, PubMed, the Cochrane Library, MEDLINE and EMBASE were searched for clinical studies on the use of vitamins in the treatment of HBV- and HCV-related hepatitis, alone or in combination with other antiviral options. Different randomised clinical trials and small case series have evaluated the potential virological and/or biochemical effects of several vitamins. The heterogeneous study designs and populations, the small number of...
The Elusive (and Maybe Non-Existent) Connection Between Vitamin B12 and HIV
Nutrition Bytes, 1996
Vitamin B12, or cobalamin, refers to any member of a group of large, cobalt-containing corrinoids and is unique among the vitamins in that it contains not only a complex organic molecule, but also an essential trace element, cobalt. Cobalamin can only be synthesized by microorganisms and is therefore present in vegetables, fruits, grains, and grain products only as a result of bacterial contamination. The main source of this vitamin is animal and, to a lesser extent, dairy products, where it can accumulate as a result of bacterial synthesis. It is also thought that some absorbable B12 is supplied by bacteria in the small intestine (National Research Council, 1993.) The small intestine is also the site for B12 absorption, where its interaction with receptor sites in the ileum is facilitated by interaction with a specific binding glycoprotein, intrinsic factor, secreted in the stomach. Another protein, transcobalamin II, is responsible for the transport of B12 from the intestinal mucosa to cells. Vitamin B12 has a long biological half life due to the fact that it is reabsorbed from the bile, a fact that explains why people who eat no animal products develop Vitamin B12 Deficiency only after 20 to 30 years (National Research Council, 1993). The problems associated with Vitamin B12 deficiency can be severe, including anemia and demyelination of the spinal cord, brain, and optic and peripheral nerves. Even among vegetarians, however, the incidence of dietary vitamin B12 deficiency are rare; most cases result from decreased absorption, often due to insufficient production of intrinsic factor.
BBA Clinical, 2014
Background: Oxidative stress in hepatitis C patients has been linked to hepatitis C virus. We verified this assumption in HCV genotype 3 patients by detecting the relationship between viral load and certain specific oxidative stress markers like Cu, Mn, Fe, Se, Zn and glutathione and glutathione-dependent enzymes. Method: Subjects (n = 200, average age 24 years) with quantitative HCV RNA polymerase chain reaction-proven genotype 3 hepatitis C were simultaneously evaluated. Cu, Mn, Fe, Se and Zn serum levels were by using atomic absorption spectrophotometer. Internationally accepted methods were used for viral load quantification of glutathione, GR and Gpx serum levels. Result: There was a significant correlation between HCV viral load and studied parameters. With the increase of viral load from mild group (200,000-1,000,000 copies/ml) to severe group (5,000,000-25,000,000 copies/ml) the serum levels of Cu, Mn, Zn, and Fe and glutathione reductase were found to be abnormally high. However, in severe viral load group serum concentration of Se and glutathione was less than the healthy controls. Conclusion: As a significant correlation was detected between the study parameters in genotype 3 HCV patients, it is concluded that the studied micronutrients and glutathione and glutathione-dependent enzymes are the biomolecular targets of HCV to induce oxidative stress. General significance: Constant monitoring and regulation of the recommended biomolecular targets of HCV can improve the plight of more than 170 million patients suffering from hepatitis C virus around the globe.
A self-modulating mechanism by the hepatitis C virus (HCV) core protein has been suggested to influence the level of HCV replication, but current data on this subject are contradictory. We examined the effect of wild-type and mutated core protein on HCV IRES- and cap-dependent translation. The wild-type core protein was shown to inhibit both IRES- and cap-dependent translation in an in vitro system. This effect was duplicated in a dose-dependent manner with a synthetic peptide representing amino acids 1-20 of the HCV core protein. This peptide was able to bind to the HCV IRES as shown by a mobility shift assay. In contrast, a peptide derived from the hepatitis B virus (HBV) core protein that contained a similar proportion of basic residues was unable to inhibit translation or bind the HCV IRES. A recombinant vaccinia-HCV core virus was used to examine the effect of the HCV core protein on HCV IRES-dependent translation in cells and this was compared with the effects of an HBV core-recombinant vaccinia virus. In CV-1 and HuH7 cells, the HCV core protein inhibited translation directed by the IRES elements of HCV, encephalomyocarditis virus and classical swine fever virus as well as cap-dependent translation, whereas in HepG2 cells, only HCV IRES-dependent translation was affected. Thus, the ability of the HCV core protein to selectively inhibit HCV IRES-dependent translation is cell-specific. N-terminal truncated (aa 1-20) HCV core protein that was expressed from a novel recombinant vaccinia virus in cells abrogated the inhibitory phenotype of the core protein in vivo, consistent with the above in vitro data.