Influence of Vitamin D in HIV Infection

There is a substantial prevalence of vitamin D deficiency (<25 nmol/L) worldwide, with estimates of 5% to 15% in high-income countries; rates of vitamin D insufficiency (<75 nmol/L) range from 50% to 75%.¹ In addition to its direct effects on bone pathologies,² increasing evidence links vitamin D deficiency to cancer, metabolic disorders, cardiovascular disease, and multiple sclerosis.³

Several studies also support a connection between vitamin D deficiency and the incidence and severity of infectious diseases, including HIV, Mycobacterium tuberculosis (TB), and hepatitis C virus (HCV).^4,5 Vitamin D “plays a global role in many physiopathological processes since [the vitamin D receptor] is expressed in tissues and cells nearly throughout the entire organism,” as noted in a recent review published in Frontiers in Immunology.¹

Risk Factors

Among HIV-infected patients, the prevalence of vitamin D deficiency is estimated to be 70% to 85%.¹ This may be, in part, because of general risk factors for deficiency, including limited sunlight exposure, female sex, black ethnicity, advanced age, and liver and kidney disease. Genetic associations with vitamin D deficiency have also been identified; for example, certain single nucleotide polymorphisms in the DBP gene appear to influence plasma vitamin D levels.^6,7

Along with these general risk factors, HIV-specific factors may contribute to vitamin D deficiency. “HIV infection itself leads to chronic inflammation and immune activation, and patients with [vitamin D] deficiency have been found to have increased [interleukin 6] and [tumor necrosis factor α] levels as well as activated monocyte phenotypes,” wrote the authors of the recent review.¹ In addition:

• Chronic inflammation may lead to “impaired 1α-hydroxylase activity in the kidneys, resulting in reduced production of 1,25(OH)₂D by blocking the PTH-stimulated conversion of 25(OH)D to 1,25(OH)₂D.”¹
• HIV-infected patients often have malnutrition, low sun exposure, and reduced consumption of foods rich in vitamin D because of hospitalizations, comorbidities, and disease-related complications.
• Protease inhibitors may reduce the conversion of 25(OH)D to 1,25(OH)₂D, and nonnucleoside reverse transcriptase inhibitors may increase catabolism of 25(OH)D.⁵ Several cross-sectional studies have observed a connection between the use of efavirenz, in particular, and vitamin D deficiency.²

Mechanisms

Various findings have demonstrated that vitamin D deficiency may influence HIV pathogenesis via negative modulation of innate and adaptive immune responses, as highlighted here.¹

• Vitamin D inhibits maturation of dendritic cells, thus preventing excessive inflammatory response to infectious diseases.
• There appears to be a link between high levels of vitamin D and its receptor and natural resistance to HIV-1 infection, possibly because of upregulation of anti-inflammatory interleukin 10 and induction of anti-HIV-1 defensins.
• Exogenous 1,25(OH)₂D in monocytes has been reported to reduce HIV susceptibility by inhibiting viral entry, decreasing CD4 expression, and limiting monocyte proliferation.
• Toll-like receptor 8 ligand agonists in human macrophages have been shown to inhibit HIV infection via a vitamin D- and cyclic adenosine monophosphate-dependent autophagic mechanism.
• In HIV-positive patients, vitamin D deficiency has been linked to increased inflammation and activated monocyte phenotypes.
• Vitamin D “may indirectly affect T-cell responses via modulation of the [dendritic cell] phenotype and its stimulatory capacity toward T cells,” as described in the article.¹ “Additionally, both naïve and resting memory T-cells express [the vitamin D receptor] at low levels, which suggests that [vitamin D] also acts directly on these T-cells.”
• Vitamin D alters T-cell phenotype and function via suppression of the Th1, Th17, and Th2 profile of cytokine production.
• Vitamin D may also reduce the capacity of [tumor necrosis factor α] to upregulate the transcription of HIV RNA from latently infected CD4⁺ cells.

Although further investigation is needed to inform the development of guidelines on this topic, limited findings indicate that vitamin D supplementation may reverse some of the immune alterations related to vitamin D deficiency.

“Preliminary data from our group showed that vitamin D supplementation in HIV-infected patients decreases immune activation, both monocyte and T-cell activation, which is at the forefront of a lot of comorbidities in HIV, such as cardiovascular disease,”⁸ Grace A. McComsey, MD, FIDSA, associate chief scientific officer at University Hospitals Health System and professor and chief of pediatric infectious diseases and rheumatology at Case Western Reserve University, Cleveland, Ohio, told Infectious Disease Advisor.

Supplementation also “improves bone density in people with HIV, in particular naive individuals starting their first medications to treat HIV,” she noted.

Experts recommend vitamin D screening [using 25(OH)D levels] for HIV-infected patients, and supplementation should be considered for those with vitamin D deficiency as well as patients initiating antiretroviral therapy or starting bisphosphonate therapy for low bone mass density.²

Future studies in this area should “investigate the role of vitamin D in prevention of long-term complications in HIV, such as cancer, diabetes, and cardiovascular disease,” stated Dr McComsey. However, it can be difficult to convince funding agencies to invest in such research, she said.

“As I always say, it is [more alluring] to study a new drug that may have tons of side effects than a safe vitamin or a generic drug with no one to profit from, except for people with chronic disease.”

References

1. Jiménez-Sousa MA, Martínez I, Medrano LM, Fernández-Rodríguez A, Resino A. Vitamin D in human immunodeficiency virus infection: influence on immunity and disease. Front Immunol. 2018;9:458.
2. Hileman CO, Overton ET, McComsey GA. Vitamin D and bone loss in HIV. Curr Opin HIV AIDS. 2016;11(3):277-284.
3. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2(1):76-89.
4. Lucas RM, Gorman S, Geldenhuys S, Hart PH. Vitamin D and immunity. F1000Prime Rep. 2014;6:118.
5. Mansueto P, Seidita A, Vitale G, Gangemi S, Iaria C, Cascio A. Vitamin D deficiency in HIV infection: not only a bone disorder. Biomed Res Int. 2015;2015:735615
6. Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376(9736):180-188.
7. Bu FX, Armas L, Lappe J, et al. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects. Hum Genet. 2010;128(5):549-556.
8. Eckard AR, O’Riordan MA, Rosebush JC, et al. Vitamin D supplementation decreases immune activation and exhaustion in HIV-1-infected youth [published online October 10, 2017]. Antivir Ther. doi: 10.3851/IMP3199