Potential effect of decreased levels of folic acid and vitamin B12 on herpes simplex virus keratitis reactivation

  • Borivoje Milan Savić Clinical Centre of Serbia, Clinic of Eye Diseases
  • Svetlana Stanojlović Clinical Center of Serbia, Clinic for Eye Diseases, Belgrade, Serbia
  • Milenko Stojković Clinical Center of Serbia, Clinic for Eye Diseases, Belgrade, Serbia
  • Miroslav Mišić College for Specialized Studies, Belgrade, Serbia
  • Božidar Savić Institute of Veterinary Medicine, Belgrade, Serbia
  • Veselin Draganić Obstetrics and Gynaecology Clinic “Narodni front”, Belgrade, Serbia
Keywords: herpesvirus 1, human;, folic acid;, keratitis;, recurrence;, risk factors;, vitamin b 12


Background/Aim. Most cases of herpetic keratitis present a recurrent disease as a result of herpes simplex virus type 1 reactivation from latency in the nearest sensory ganglia. Therefore, understanding the mechanisms of latency and reactivation of the latent virus is an important link in comprehending the onset of the recurrent eye disease itself. Epigenetic regulation of virus reactivation, as a result of the presence of transcriptionally active Latency-Associated Transcript (LAT) region in the latent viral genome, has already been demonstrated in several studies. The activity of the LAT region is directed to the chromatin arrangement. Epigenetic modulation of DNA methylation is associated with folate and vitamin B12 intake or their serum concentrations. To our knowledge, there is no report on the potential role of vitamin B12 and folic acid in herpes simplex virus keratitis reactivation. The aim of this study was to analyze the potential role of folic acid and vitamin B12 in the control of ocular herpes simplex keratitis reactivation. Methods. The study included 50 patients older than 18 years of age with recurrent herpes simplex virus eye disease. Levels of vitamin B12 and folic acid were measured in the acute phase of the disease. All patients were followed up for at least one year and episodes of recurrent herpetic eye diseases were recorded. Results. The recurrence rate of herpetic keratitis was statisticall significantly lower in patients with a higher blood level of vitamin B12. In addition, the recurrence rate of herpetic keratitis was lower in patients with a higher blood level of folic acid. However, statistical significance was lower in comparison with that for vitamin B12. Conclusion. The decreased levels of vitamin B12 and folic acid might have a vital role in herpes simplex keratitis reactivation.


Rabenau HF, Buxbaum S, Preiser W, Weber B, Doerr HW. Sero-prevalence of herpes simplex virus types 1 and type 2 in the Frankfurt am Main area, Germany. Med Microbiol Immu-nol 2002; 190(4): 153–60.

Xu F, Sternberg MR, Kottiri BJ, McQuillan GM, Lee FK, Nahmi-as AJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA 2006; 296(8): 964‒73.

Young RC, Hodge DO, Liesegang TJ, Baratz KH. Incidence, re-currence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976–2007: the effect of oral antiviral prophylaxis. Arch Ophthalmol 2010; 128(9): 1178–83.

Labetoulle M, Auquier P, Conrad H, Crochard A, Daniloski M, Bouee S, et al. Incidence of herpes simplex virus keratitis in France. Ophthalmology 2005; 112(5): 888–95.

Darougar S, Wishart MS, Viswalingam ND. Epidemiological and clinical features of primary herpes simplex virus ocular in-fection. Br J Ophthalmol 1985; 69(1): 2–6.

Shimeld C, Hill TJ, Blyth WA, Easty DL. Passive immunization protects the mouse eye from damage after herpes simplex vi-rus infection by limiting spread of virus in the nervous sys-tem. J Gen Virol 1990; 71(Pt 3): 681–7.

Shimeld C, Hill TJ, Blyth WA, Easty DL. Reactivation of latent infection and induction of recurrent herpetic eye disease in mice. J Gen Virol 1990; 71(Pt 2): 397–404.

Jones BR. The clinical features of viral keratitis and a concept of their pathogenesis. Proc R Soc Med 1958; 51(11): 917–24.

Umbach JL, Kramer MF, Jurak I, Karnowski HW, Coen DM, Cul-len BR. MicroRNAs expressed by herpes simplex virus 1 dur-ing latent infection regulate viral mRNAs. Nature 2008; 454(7502): 780– 3.

Bertke AS, Swanson SM, Chen J, Imai Y, Kinchington PR, Margolis TP. A5-positive primary sensory neurons are nonpermissive for productive infection with herpes simplex virus 1 in vitro. J Virol 2011; 85(13): 6669–77.

Yang L, Voytek CC, Margolis TP. Immunohistochemical analy-sis of primary sensory neurons latently infected with herpes simplex virus type 1. J Virol 2000; 74(1): 209–17.

Anderson OS, Sant KE, Dolinoy DC. Nutrition and epigenetic: An interplay of dietary methyl donors, one-carbon metabo-lism, and DNA methylation. J Nutr Biochem 2012; 23(8): 853–9.

Maclatchy RS. Herpes ophthalmicus. Br J Ophthalmol 1956; 40(12): 762–4.

Rossler H. Zur Behandlung des Herpes zoster ophthalmicus. Klin Mbl Augenheilk 1956; 128: 727. (German)

Piyathilake CJ, Macaluso M, Chambers MM, Badiga S, Siddiqui NR, Bell WC, et al. Folate and vitamin B12 may play a critical role in lowering the HPV 16 methylation-associated risk of developing higher grades of CIN. Cancer Prev Res (Phi-la) 2014; 7(11): 1128‒37.

Lopes RDVC, Teixeira JA, Marchioni D, Villa LL, Giuliano AR, Luiza Baggio M, Fisberg RM. Dietary intake of selected nutrients and persistence of HPV infection in men. Int J Can-cer 2017; 141(4): 757‒65.

Ślebioda Z, Krawiecka E, Szponar E, Dorocka-Bobkowska B. Haematinic deficiencies and patient clinical profiles in Polish patients with recurrent aphthous stomatitis (RAS). J Oral Pathol Med 2018; 47(5): 531‒7.

Bloom DC, Giordani NV, Kwiatkowski DL. Epigenetic regula-tion of latent HSV-1 gene expression. Biochim Biophys Acta 2010; 1799(3‒4): 246‒56.

Cliffe AR, Garber DA, Knipe DM. Transcription of the herpes simplex virus latency-associated transcript promotes the for-mation of facultative heterochromatin on lytic promoters. J Virol 2009; 83(16): 8182–90.

Blyth WA, Hill TJ, Field HJ, Harbour DA. Reactivation of her-pes simplex virus infection by ultraviolet light and possible in-volvement of prostaglandins. J Gen Virol 1976; 33(3): 547–50.

Bonneau RH, Sheridan JF, Feng N, Glaser R. Stress-induced modulation of the primary cellular immune response to herpes simplex virus infection is mediated by both adrenal-dependent and independent mechanisms. J Neuroimmunol 1993; 42(2): 167–76.

Sainz B, Loutsch JM, Marquart ME, Hill JM. Stress-associated immunomodulation and herpes simplex virus infections. Med Hypotheses 2001; 56(3): 348–56.

Vicetti Miguel RD, Sheridan BS, Harvey SA, Schreiner RS, Hen-dricks RL, Cherpes TL. 17-beta estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor depend-ent. J Virol 2010; 84(1): 565–72.

Gebhardt BM, Hill JM. T lymphocytes in the trigeminal ganglia of rabbits during corneal HSV infection. Invest Ophthalmol Vis Sci 1988; 29(11): 1683–691.

Liu T, Tang Q, Hendricks RL. Inflammatory infiltration of the trigeminal ganglion after herpes simplex virus type 1 corneal infection. J Virol 1996; 70(1): 264–71.

Original Paper