Possible roles for vitamin D in selected infections—TB, colds and flu, HIV, hepatitis C virus and bacterial vaginosis
Lab experiments with cells of the immune system—monocytes and macrophages—have found that these cells produce an enzyme that converts vitamin D into its active form. This suggests that these cells use vitamin D as part of the process of fighting infections and possibly tumours. Other experiments have found that exposure to vitamin D3 stimulates macrophages to release small molecules that can attack germs.
Before potent antibiotics were available, physicians encouraged people with TB to get exposure to sunlight and in some cases vitamin D supplements were administered. However, well-designed clinical trials in the 21st century have found that vitamin D supplements in addition to antibiotics do not confer a major increase in survival or recovery from TB compared to antibiotics alone. Some researchers have suggested that instead of being used as part of treatment, perhaps vitamin D supplements might be more useful in helping to prevent infection with TB. Clinical trials to test this idea have not been done.
Colds and flu
Cells lining the lungs can produce high levels of enzymes that convert vitamin D into its active form, vitamin D3. This finding suggests that these cells may use vitamin D as part of their defense system against infections. Indeed, in laboratory experiments when these cells are treated with vitamin D3, they also produce small molecules that help protect cells from infection by viruses and bacteria.
Several clinical trials that have tested vitamin D3 to assess its ability to reduce the risk of developing respiratory tract infections—the common cold and flu—have had mixed results. It is therefore difficult to draw firm conclusions about the role of vitamin D in preventing respiratory infections. Part of the problem arises from issues related to different study designs and methodology.
Observational studies have found that HIV-positive people usually have less-than-ideal levels of vitamin D in the blood and, in some cases, deficiency. Vitamin D deficiency in the setting of HIV infection even occurs in sunny tropical countries. Researchers are not certain why this is the case. One possible explanation is that HIV infection triggers ongoing inflammation in the immune system. By inciting the immune system to overproduce inflammation-related chemical signals or cytokines, it is possible that HIV infection indirectly speeds up enzymes that convert vitamin D3 into inactive forms.
Supplementation with large amounts of vitamin D does not increase HIV replication in people who are taking ART. Results from two clinical trials suggest that vitamin D3 does not affect CD4+ cell counts in HIV-positive adults and children.
Larger observational studies have found that vitamin D deficiency has been linked to an increased risk of death among HIV-negative people, particularly from cardiovascular disease. A recent European study with about 2,000 participants has found an association between low vitamin D levels and reduced survival among HIV-positive people. Details about this study appear in TreatmentUpdate 181. As the study is observational in nature, it cannot prove that low vitamin D levels are the cause of death. However, the same European researchers are also conducting a large study of vitamin D supplementation, hoping to improve survival rates in HIV-positive people. Interim results from this study of supplementation should be available in several years.
Researchers have found associations between low levels of vitamin D and pre-diabetes or diabetes in HIV-positive people in several studies. However, it is not clear if vitamin D deficiency led to problems with insulin and blood sugar. Clinical trials are needed to understand the relationship between vitamin D supplementation and pre-diabetes or diabetes in HIV-positive people.
Hepatitis C virus (HCV)—antiviral and other effects
Researchers in Israel have performed laboratory experiments with vitamin D, liver cells and HCV. In these experiments, treating HCV-infected cells with vitamin D3 reduced their production of this virus, likely by stimulating the release of interferon. Treating these cells with low concentrations of both vitamin D3 and interferon-alpha also reduced HCV production.
Note that lab experiments with cells and viruses do not reproduce the complexity of an organ or system. These experiments are an interesting first step on the path to conducting further experiments with vitamin D3 and HCV-infected cells. Hopefully they will eventually lead to clinical trials.
Studies with HCV-infected people suggest that some of those with vitamin D deficiency are less likely to respond to HCV therapy than people with higher concentrations of vitamin D in their blood. Also, vitamin D is associated with a reduced risk of rejecting transplanted liver. Vitamin D is also associated with reduced liver inflammation in HCV infection. Unfortunately, due to the observational nature of these studies, firm conclusions about vitamin D’s effects cannot be drawn at this time. Such findings need to be confirmed in robustly designed clinical trials so that the role of vitamin D in HCV infection can be better understood.
The vagina normally contains a mix of mostly good bacteria and small amounts of bad bacteria. Sometimes women develop an imbalance in the bacteria that live in their vagina, whereby the proportion of bad bacteria increases—bacterial vaginosis (BV). In cases of BV, women can experience such symptoms as itching, burning, pain and discharge, while in some cases BV can occur without causing symptoms. BV does not normally cause serious complications, however, it can do so in cases where the woman is pregnant. BV can increase the risk for HIV transmission and the risk for becoming infected with STIs.
Observational studies have found an association between BV in pregnant, HIV-negative women and vitamin D deficiency. Recently, in a study of 600 non-pregnant women, researchers in the U.S. found an association between BV and vitamin D deficiency among women who were HIV positive. As with so many studies of vitamin D, this was an observational study so it can only find associations and does not prove that vitamin D deficiency causes BV. Indeed, in general, researchers are not certain why some women develop BV, though there are several theories. The present study provides a foundation to conduct more rigorous research to explore this link between BV and vitamin D, particularly among HIV-positive women.
—Sean R. Hosein
- Holick MF, Binkley NC, Hike A, et al. Evaluation, treatment and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology and Metabolism. 2011 Jul;96(7):1911-30.
- Kresfelder TL, Janssen R, Bont L, et al. Confirmation of an association between single nucleotide polymorphisms in the VDR gene with respiratory syncytial virus related disease in South African children. Journal of Medical Virology. 2011 Oct;83(10):1834-40.
- Lagishetty V, Liu NQ, Hewison M. Vitamin D metabolism and innate immunity. Molecular and Cellular Endocrinology. 2011 Jun 1. [Epub ahead of print]
- McMahon L, Schwartz K, Yilmaz O, et al. Vitamin D-mediated induction of innate immunity in gingival epithelial cells. Infection and Immunity. 2011 Jun;79(6):2250-6.
- Selvaraj P. Vitamin D, vitamin D receptor, and cathelicidin in the treatment of tuberculosis. Vitamins and Hormones. 2011;86:307-25.
- Hewison M. Antibacterial effects of vitamin D. Nature Reviews. Endocrinology. 2011 Jun;7(6):337-45.
- Beard JA, Bearden A, Striker R. Vitamin D and the anti-viral state. Journal of Clinical Virology. 2011 Mar;50(3):194-200.
- Shaman J, Jeon CY, Giovannucci E, et al. Shortcomings of vitamin D-based model simulations of seasonal influenza. PLoS One. 2011;6(6):e20743.
- Roth DE, Soto G, Arenas F, et al. Association between vitamin D receptor gene polymorphisms and response to treatment of pulmonary tuberculosis. Journal of Infectious Diseases. 2004 Sep 1;190(5):920-7.
- White JH. Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. Journal of Steroid Biochemistry and Molecular Biology. 2010 Jul;121(1-2):234-8.
- Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006 Mar 24;311(5768):1770-3.
- Ní Cheallaigh C, Keane J, Lavelle EC, et al. Autophagy in the immune response to tuberculosis: clinical perspectives. Clinical and Experimental Immunology. 2011 Jun;164(3):291-300.
- Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet. 2011 Jan 15;377(9761):242-50.
- Vieth R. Vitamin D nutrient to treat TB begs the prevention question. Lancet. 2011 Jan 15;377(9761):189-90.
- Handel AE, Ramagopalan SV. Tuberculosis and diabetes mellitus: Is vitamin D the missing link? Lancet Infectious Diseases. 2010 Sep;10(9):596.
- Hewison M. Vitamin D and the immune system: new perspectives on an old theme. Endocrinology and Metabolism Clinics of North America. 2010 Jun;39(2):365-79.
- Talat N, Perry S, Parsonnet J, et al. Vitamin D deficiency and tuberculosis progression. Emerging Infectious Diseases. 2010 May;16(5):853-5.
- Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind, randomized, placebo-controlled trial. American Journal of Respiratory and Critical Care Medicine. 2009 May 1;179(9):843-50.
- Haug CJ, Aukrust P, Haug E, et al. Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. Journal of Clinical Endocrinology and Metabolism. 1998 Nov;83(11):3832-8.
- Haug C, Müller F, Aukrust P, et al. Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: correlation with degree of immune deficiency and survival. Journal of Infectious Diseases. 1994 Apr;169(4):889-93.
- French AL, Adeyemi OM, Agniel DM, et al. Bacterial vaginosis and vitamin D deficiency among nonpregnant HIV-infected and uninfected women in the United States. Journal of Women’s Health (Larchmt). 2011 Aug 29. [Epub ahead of print]
- Vescini F, Cozzi-Lepri A, Borderi M, et al. Prevalence of hypovitaminosis D and factors associated with vitamin D deficiency and morbidity among HIV-infected patients enrolled in a large Italian cohort. Journal of Acquired Immune Deficiency Syndromes. 2011 Aug 4. [Epub ahead of print]
- Mueller NJ, Fux CA, Ledergerber B, et al. High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS. 2010 May 15;24(8):1127-34.
- Kakalia S, Sochett EB, Stephens D, et al. Vitamin D supplementation and CD4 count in children infected with Human Immunodeficiency Virus. Journal of Pediatrics. 2011 Aug 3. [Epub ahead of print]
- Hammond E, McKinnon E, Glendenning P, et al. Association between 25-OH vitamin D and insulin is independent of lipoatrophy in HIV. Clin Endocrinol (Oxf). 2011 Jun 17. [Epub ahead of print]
- Lake JE, Adams JS. Vitamin D in HIV-infected patients. Current HIV/AIDS Reports. 2011 Sep;8(3):133-41.
- Viard JP, Souberbielle JC, Kirk O, et al. Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study. AIDS. 2011 Jun 19;25(10):1305-15.
- Conrado T, Miranda-Filho Dde B, et al. Vitamin D deficiency in HIV-infected women on antiretroviral therapy living in the tropics. Journal of the International Association of Physicians in AIDS Care. 2011 Jul-Aug;10(4):239-45.
- Adeyemi OM, Agniel D, French AL, et al. Vitamin D deficiency in HIV-infected and HIV-uninfected women in the United States. Journal of Acquired Immune Deficiency Syndromes. 2011 Jul 1;57(3):197-204.
- Hensel KJ, Randis TM, Gelber SE, et al. Pregnancy-specific association of vitamin D deficiency and bacterial vaginosis. American Journal of Obstetrics and Gynecology. 2011 Jan;204(1):41.e1-9.
- Campbell GR, Spector SA. Hormonally active vitamin D3 (1alpha,25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection. Journal of Biological Chemistry. 2011 May 27;286(21):18890-902.
- Gharakhanian S, Kotler DP. Diabetes mellitus, HIV infection, and vitamin D: time to act or time to think? AIDS. 2011 Feb 20;25(4):531-3
- Dao CN, Patel P, Overton ET, et al. Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the U.S. general population. Clinical Infectious Diseases. 2011 Feb 1;52(3):396-405.
- Szep Z, Guaraldi G, Shah SS, et al. Vitamin D deficiency is associated with type 2 diabetes mellitus in HIV infection. AIDS. 2011 Feb 20;25(4):525-9.
- Fox J, Peters B, Prakash M, et al. Improvement in vitamin D deficiency following antiretroviral regime change: Results from the MONET trial. AIDS Research and Human Retroviruses. 2011 Jan;27(1):29-34.
- Rosenvinge MM, Gedela K, Copas AJ, et al. Tenofovir-linked hyperparathyroidism is independently associated with the presence of vitamin D deficiency. Journal of Acquired Immune Deficiency Syndromes. 2010 Aug 15;54(5):496-9.
- Lattuada E, Lanzafame M, Zoppini G, et al. No influence of nevirapine on vitamin D deficiency in HIV-infected patients. AIDS Research and Human Retroviruses. 2009 Aug;25(8):849-50.
- Gal-Tanamy M, Bachmetov L, Ravid A, et al. Vitamin-D: An innate antiviral agent suppressing Hepatitis C virus in human hepatocytes. Hepatology. 2011 Jul 25. [Epub ahead of print]
- Bitetto D, Fabris C, Falleti E, et al. Vitamin D deficiency and HCV chronic infection: What comes first? Journal of Hepatology. 2011 Feb 22. [Epub ahead of print]
- Terrier B, Carrat F, Geri G, et al. Low 25-OH vitamin D serum levels correlate with severe fibrosis in HIV-HCV co-infected patients with chronic hepatitis. Journal of Hepatology. 2011 Feb 18. [Epub ahead of print]
- Lange CM, Bojunga J, Ramos-Lopez E, 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. Journal of Hepatology. 2011 May;54(5):88.