About antiviral effects of vitamin D

Preventing infectious diseases is very important in obstetric and gynaecological practice. Vitamin D is a complex regulator of innate and adaptive immunity. It is known that lack of vitamin D reduces antibacterial and antiviral immunity, stimulates the development of pathologies associated with chronic systemic inflammation. Evidence from evidence-based medicine indicates the importance of using vitamin D preparations to support immunity. The results of fundamental and clinical studies have shown that chronic inflammation and congenital immunity disorders resulting from vitamin D deficiency significantly reduce the body’s resistance not only to tuberculosis, but also to viral hepatitis, acute respiratory infections, papillomavirus and herpesvirus. In addition to a pronounced antibacterial effect, vitamin D is also characterized by its antiviral action. By increasing the expression of interferon-alpha, cathecidine, defensin and antiviral microRNA, vitamin D activates various mechanisms of congenital antiviral immunity. Studies show the need to compensate for vitamin D deficiency for successful therapy of viral hepatitis, respiratory infections, human papillomavirus (HPV) and herpesvirus. In the present article the molecular fundamentals of antiviral action of vitamin D are sequentially considered, as well as the results of fundamental and clinical studies indicating the action of vitamin D against the viruses of hepatitis, herpes, RSV, Epstein-Barr, human papillomavirus, the possibility of using vitamin D in the treatment of these and other viral pathologies is considered. The authors analyzed data on the effect of vitamin D on immunity functions and antiviral protection of the human body.

1. Gromova O.A., Torshin I.Yu. Vitamin D – paradigm shift. Moscow: GEOTARMedia, 568 p. (In Russ.) Available at: https://www.rosmedlib.ru/book/ISBN9785970440582.html.

2. Sundaram M.E., Coleman L.A. Vitamin D and influenza. Adv Nutr. 2012;3(4):517–525. doi: 10.3945/an.112.002162.

3. Khoo A.L., Chai L.Y., Koenen H.J.P.M., Oosting M., Steinmeyer A., Zuegel U. et al. Vitamin D(3) down-regulates proinflammatory cytokine response to Mycobacterium tuberculosis through pattern recognition receptors while inducing protective cathelicidin production. Cytokine. 2011;55(2):294–300. doi: 10.1016/j.cyto.2011.04.016.

4. Lin Y.T., Wang L.K., Hung K.C., Wu Z.F., Chang C.Y., Chen J.Y. Patient characteristics and analgesic efficacy of antiviral therapy in postherpetic neuralgia. Med Hypotheses. 2019;131:109323. doi: 10.1016/j.mehy.2019.109323.

5. El-Taweel A.E., Salem R.M., Allam A.H. Cigarette smoking reduces the efficacy of intralesional vitamin D in the treatment of warts. Dermatol Ther. 2019;32(2):e12816. doi: 10.1111/dth.12816.

6. Oztekin A., Oztekin C. Vitamin D Levels in Patients with Recurrent Herpes Labialis. Viral Immunol. 2019;32(6):258–262. doi: 10.1089/vim.2019.0013.

7. Ozgu E., Yilmaz N., Baser E., Gungor T., Erkaya S., Yakut H.I. Could 25-OH vitamin D deficiency be a reason for HPV infection persistence in cervical premalignant lesions? J Exp Ther Oncol. 2016;11(3):177–180. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28471122.

8. Gutierrez J.A., Jones K.A., Flores R., Singhania A., Woelk C.H., Schooley R.T., Wyles D.L. Vitamin D Metabolites Inhibit Hepatitis C Virus and Modulate Cellular Gene Expression. J Virol Antivir Res. 2014;3(3). doi: 10.4172/23248955.1000129.

9. Beard J.A., Bearden A., Striker R. Vitamin D and the anti-viral state. J Clin Virol. 2011;50(3):194–200. doi: 10.1016/j.jcv.2010.12.006.

10. Kamen D.L., Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med. 2010;88(5):441–450. doi: 10.1007/s00109-010-0590-9.

11. Korucu E., Pur Ozyigit L., Ortakoylu M.G., Bahadir A., Akalin E.S., Kara A. et al. Cathelicidin as a link between sarcoidosis and tuberculosis. Sarcoidosis Vasc Diffuse Lung Dis. 2015;32(3):222–227. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26422567.

12. Jeng L., Yamshchikov A.V., Judd S.E., Blumberg H.M., Martin G.S., Ziegler T.R., Tangpricha V. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009;7:28. doi: 10.1186/1479-5876-7-28.

13. Gombart A.F., Bhan I., Borregaard N., Tamez H., Camargo C.A. Jr, Koeffler H.P., Thadhani R. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin Infect Dis. 2009;48(4):418–424. doi: 10.1086/596314.

14. Arboleda J.F., Urcuqui-Inchima S. Vitamin D-Regulated MicroRNAs: Are They Protective Factors against Dengue Virus Infection? Adv Virol. 2016;2016:1016840. doi: 10.1155/2016/1016840.

15. Duan X., Guan Y., Li Y., Chen S., Li S., Chen L. Vitamin D Potentiates the Inhibitory Effect of MicroRNA-130a in Hepatitis C Virus Replication Independent of Type I Interferon Signaling Pathway. Mediators Inflamm. 2015;2015:508989. doi: 10.1155/2015/508989.

16. Looman K.I.M., Jansen M.A.E., Voortman T., van den Heuvel D., Jaddoe V.W.V., Franco O.H. et al. The role of vitamin D on circulating memory T cells in children: The Generation R study. Pediatr Allergy Immunol. 2017;28(6):579– 587. doi: 10.1111/pai.12754.

17. Matsumura T., Kato T., Sugiyama N., Tasaka-Fujita M., Murayama A., Masaki T. et al. 25-Hydroxyvitamin D3 suppresses hepatitis C virus production. Hepatology. 2012;56(4):1231–1239. doi: 10.1002/hep.25763.

18. Huang J.F., Ko Y.M., Huang C.F., Yeh M.L., Dai C.Y., Hsieh M.H. et al. 25-Hydroxy vitamin D suppresses hepatitis C virus replication and contributes to rapid virological response of treatment efficacy. Hepatol Res. 2017;47(13):1383–1389. doi: 10.1111/hepr.12878.

19. Petta S., Camma C., Scazzone C., Tripodo C., Di Marco V., Bono A. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51(4):1158–1167. doi: 10.1002/hep.23489.

20. Lange C.M., Bojunga J., Ramos-Lopez E., von Wagner M., Hassler A., Vermehren J. et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol. 2011;54(5):887–889. doi: 10.1016/j.jhep.2010.08.036.

21. Villar L.M., Del Campo J.A., Ranchal I., Lampe E., Romero-Gomez M. Association between vitamin D and hepatitis C virus infection: a metaanalysis. World J Gastroenterol. 2013;19(35):5917–5924. doi: 10.3748/wjg.v19.i35.5917.

22. Garcia-Alvarez M., Pineda-Tenor D., Jimenez-Sousa M.A., FernandezRodriguez A., Guzman-Fulgencio M., Resino S. Relationship of vitamin D status with advanced liver fibrosis and response to hepatitis C virus therapy: a meta-analysis. Hepatology. 2014;60(5):1541–1550. doi: 10.1002/hep.27281.

23. Kim H.B., Myung S.K., Lee Y.J., Park B.J. Efficacy of vitamin D supplementation in combination with conventional antiviral therapy in patients with chronic hepatitis C infection: a meta-analysis of randomised controlled trials. Journal of Human Nutrition and Dietetics. 2018;31(2):168–177. doi: 10.1111/jhn.12503.

24. Zdrenghea M.T., Makrinioti H., Bagacean C., Bush A., Johnston S.L., Stanciu L.A. Vitamin D modulation of innate immune responses to respiratory viral infections. Rev Med Virol. 2017;27(1):e1909. doi: 10.1002/rmv.1909.

25. Telcian A.G., Zdrenghea M.T., Edwards M.R., Laza-Stanca V., Mallia P., Johnston S.L., Stanciu L.A. Vitamin D increases the antiviral activity of bronchial epithelial cells in vitro. Antiviral Res. 2017;137:93–101. doi: 10.1016/j.antiviral.2016.11.004.

26. Hurwitz J.L., Jones B.G., Penkert R.R., Gansebom S., Sun Y., Tang L. et al. Low Retinol-Binding Protein and Vitamin D Levels Are Associated with Severe Outcomes in Children Hospitalized with Lower Respiratory Tract Infection and Respiratory Syncytial Virus or Human Metapneumovirus Detection. J Pediatr. 2017;187:323–327. doi: 10.1016/j.jpeds.2017.04.061.

27. Hansdottir S., Monick M.M., Lovan N., Powers L., Gerke A., Hunninghake G.W. Vitamin D decreases respiratory syncytial virus induction of NF-kappaBlinked chemokines and cytokines in airway epithelium while maintaining the antiviral state. J Immunol. 2010;184(2):965–974. doi: 10.4049/jimmunol.0902840.

28. Martineau A.R., Jolliffe D.A., Hooper R.L., Greenberg L., Aloia J.F., Bergman P. et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. doi: 10.1136/bmj.i6583.

29. Zhu M., Wang T., Wang C., Ji Y. The association between vitamin D and COPD risk, severity, and exacerbation: an updated systematic review and meta-analysis. Int J Chron Obstruct Pulmon Dis. 2016;11(1):2597–2607. doi: 10.2147/COPD.S101382.

30. Thappa D.M., Chiramel M.J. Evolving role of immunotherapy in the treatment of refractory warts. Indian Dermatol Online J. 2016;7(5):364–370. doi: 10.4103/2229-5178.190487.

31. Zimmerman R.K., Lin C.J., Raviotta J.M., Nowalk M.P. Do vitamin D levels affect antibody titers produced in response to HPV vaccine? Hum Vaccin Immunother. 2015;11(10):2345–2349. doi: 10.1080/21645515.2015.1062955.

32. Shim J., Perez A., Symanski E., Nyitray A.G. Association Between Serum 25-Hydroxyvitamin D Level and Human Papillomavirus Cervicovaginal Infection in Women in the United States. J Infect Dis. 2016;213(12):1886– 1892. doi: 10.1093/infdis/jiw065.

33. Vahedpoor Z., Jamilian M., Bahmani F., Aghadavod E., Karamali M., Kashanian M., Asemi Z. Effects of Long-Term Vitamin D Supplementation on Regression and Metabolic Status of Cervical Intraepithelial Neoplasia: a Randomized, Double-Blind, Placebo-Controlled Trial. Horm Cancer. 2017;8(1):58–67. doi: 10.1007/s12672-016-0278-x.

34. Hosono S., Matsuo K., Kajiyama H., Hirose K., Suzuki T., Kawase T. et al. Association between dietary calcium and vitamin D intake and cervical carcinogenesis among Japanese women. Eur J Clin Nutr. 2010;64(4):400– 409. doi: 10.1038/ejcn.2010.28.

35. Kumar A., Singh M.P., Kumar R.S., Ratho R.K. 25-Hydroxyvitamin D3 and 1,25 Dihydroxyvitamin D3 as an Antiviral and Immunomodulator Against Herpes Simplex Virus-1 Infection in HeLa Cells. Viral Immunol. 2018;31(8):589–593. doi: 10.1089/vim.2018.0026.

36. Suares A., Tapia C., Gonzalez-Pardo V. VDR agonists down regulate PI3K/ Akt/mTOR axis and trigger autophagy in Kaposi’s sarcoma cells. Heliyon. 2019;5(8):e02367. doi: 10.1016/j.heliyon.2019.e02367.

37. Suares A., Tapia C., Gonzalez-Pardo V. Antineoplastic effect of 1alpha, 25(OH)2D3 in spheroids from endothelial cells transformed by Kaposi’s sarcomaassociated herpesvirus G protein coupled receptor. J Steroid Biochem Mol Biol. 2019;186:122–129. doi: 10.1016/j.jsbmb.2018.10.004.

38. Mostafa A., Jalilvand S., Shoja Z., Nejati A., Shahmahmoodi S., Sahraian M.A., Marashi S.M. Multiple sclerosis-associated retrovirus, Epstein-Barr virus, and vitamin D status in patients with relapsing remitting multiple sclerosis. J Med Virol. 2017;89(7):1309–1313. doi: 10.1002/jmv.24774.

39. Perez-Perez S., Dominguez-Mozo M.I., Garcia-Martinez M.A., Aladro Y., Martinez-Gines M., Garcia-Dominguez J.M. et al. Study of the possible link of 25-hydroxyvitamin D with Epstein-Barr virus and human herpesvirus 6 in patients with multiple sclerosis. Eur J Neurol. 2018;25(12):1446–1453. doi: 10.1111/ene.13749.

40. Teymoori-Rad M., Mozhgani S.H., Zarei-Ghobadi M., Sahraian M.A., Nejati A., Amiri M.M. et al. Integrational analysis of miRNAs data sets as a plausible missing linker between Epstein-Barr virus and vitamin D in relapsing remitting MS patients. Gene. 2019;689:1–10. doi: 10.1016/j.gene.2018.12.004.

41. Abdel-Wahab N., Talathi S., Lopez-Olivo M.A., Suarez-Almazor M.E. Risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis. Lupus. 2018;27(4):572–583. doi: 10.1177/0961203317731532.

42. Kim Y., Kim H.S., Park J.S., Kim C.J., Kim W.H. Identification of Epstein-Barr Virus in the Human Placenta and Its Pathologic Characteristics. J Korean Med Sci. 2017;32(12):1959–1966. doi: 10.3346/jkms.2017.32.12.1959.

43. Elliott S.E., Parchim N.F., Kellems R.E., Xia Y., Soffici A.R., Daugherty P.S. A pre-eclampsia-associated Epstein-Barr virus antibody cross-reacts with placental GPR50. Clin Immunol. 2016;168:64–71. doi: 10.1016/j.clim.2016.05.002.