Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease

Abstract

People living with human immunodeficiency virus (HIV) infection typically have hypovitaminosis D, which is linked to a large number of pathologies, including immune disorders and infectious diseases. Vitamin D (VitD) is a key regulator of host defense against infections by activating genes and pathways that enhance innate and adaptive immunity. VitD mediates its biological effects by binding to the Vitamin D receptor (VDR), and activating and regulating multiple cellular pathways. Single nucleotide polymorphisms in genes from those pathways have been associated with protection from HIV-1 infection. High levels of VitD and VDR expression are also associated with natural resistance to HIV-1 infection. Conversely, VitD deficiency is linked to more inflammation and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients. VitD supplementation and restoration to normal values in HIV-infected patients may improve immunologic recovery during combination antiretroviral therapy, reduce levels of inflammation and immune activation, and increase immunity against pathogens. Additionally, VitD may protect against the development of immune reconstitution inflammatory syndrome events, pulmonary tuberculosis, and mortality among HIV-infected patients. In summary, this review suggests that VitD deficiency may contribute to the pathogenesis of HIV infection. Also, VitD supplementation seems to reverse some alterations of the immune system, supporting the use of VitD supplementation as prophylaxis, especially in individuals with more severe VitD deficiency.

Keywords: adaptive immunity; human immunodeficiency virus; immune activation; inflammation; innate immunity; vitamin D deficiency.

Figure 1

Schematic of the synthesis of vitamin D (VitD) in the body. Cutaneous 7-dihydrocholesterol is converted into preVitD₃ following irradiation by ultraviolet light from the sun (2). Next, preVitD₃ forms cholecalciferol (VitD₃) by spontaneous isomerization. Subsequently, cholecalciferol is hydroxylated to 25-hydroxy-VitD (25(OH)D) or calcidiol, mainly in the liver, by the cytochrome P450 hydroxylase enzymes CYP27A1 and CYP2R1. Then, 25(OH)D is transported to the kidneys, where it is hydroxylated at the 1 alpha position by the 25-hydroxy-VitD-1 alpha hydroxylase (CYP27B1) to generate 1,25-dihydroxycholecalciferol [1,25 (OH)₂D] or calcitriol, which is the metabolically active compound (1, 2). Hydroxyvitamin D-24-hydroxylase (CYP24A1) is the enzyme responsible for the multi-step catabolism of both 25(OH)D and 1,25 (OH)₂D. The main product of 25(OH)D catabolism by CYP24A1 is 24,25-dihydroxycholecalciferol [24,25(OH)₂D], which is less active than calcitriol and presumably represents a metabolite destined for excretion. Importantly, VitD is not only converted from 25(OH)D to 1,25 (OH)₂D in the kidney but it is also activated locally by CYP27B1 in many tissues, including the brain, smooth muscle, breast, and prostate as well as cells of the immune system.

Figure 2

Schematic of transport and mechanism of action of vitamin D (VitD) in the body. (A) A small fraction of VitD circulates in the serum as a “free” steroid, having easy access to the intracellular compartment. The remaining VitD is transported in the blood while bound to the vitamin D-binding protein (DBP) (1, 2), which seems to critically regulate the bioavailability of VitD (7). This protein-bound fraction (bound to DBP) is actively transported into the cell by megalin or cubulin. Calcitriol is considered the main ligand of the vitamin D receptor (VDR) to trigger the effects of VitD, because its affinity is 1,000 times greater than calcidiol (8). When VitD binds to VDR in the nucleus of target cells, it forms a complex with the retinoic acid X receptor (RXR), which controls transcriptional activity of target genes. This heterodimer binds to VitD response elements (VDREs), a predefined promoter DNA sequence, initiating gene transcription processes, which covers around 5% of the human genome and 36 different cell types (4). However, there are genes regulated by VitD that do not contain VDREs (9). These genes may be regulated by microRNAs, phosphorylation, or other modifications of proteins, which affect their stability or the activity of proteases that target them (9). Additionally, non-genomic effects have been reported when the VDR is situated on the cell membrane (VDRm) complexed to caveolin (5), which immediately activates several intracellular pathways, such as mitogen-activated protein kinases, protein kinase C (PKC), protein kinase A, and Ca2+-calmodulin kinase II through the activation of several signaling molecules (5). VitD may reduce its synthesis by inhibiting CYP27B1 and increases its degradation by inducing CYP24A1 (6). (B) VitD modulates the function of monocytes/macrophages and dendritic cells (DCs) in response to infections. In monocytes/macrophages, 1,25(OH)₂D leads to the expression of multi-target genes, among which are cathelicidin microbial peptide (10, 11), human β-defensin 4 (DEFB4) (12), and genes involved in autophagy and phagosome maturation, all of which are involved in the intracellular destruction of pathogens (7, 13). Furthermore, 1,25(OH)₂D enhances the chemotactic and phagocytic capacity of macrophages (14). Moreover, VitD also promotes an anti-inflammatory response by inhibiting the maturation of DCs, resulting in a phenotype characterized by the downregulation of antigen presenting molecules (MHC-class II), costimulatory molecules (e.g., CD40, CD80, and CD86), and pro-inflammatory cytokines (e.g., IL-12 and IL-23); while an anti-inflammatory cytokine (IL-10) and T-cell inhibitory molecule (PD-1) are enhanced (–22). Therefore, VitD induces hypo-responsiveness and allows a shift in the T-cell polarization from the pro-inflammatory Th1 and Th17 responses to a more tolerogenic Th2 response (, , , –24), which leads to an altered alloreactive T cell activation (25). (C) VitD induces anti-inflammatory responses through direct effects on T-cells. Specifically, 1,25(OH)₂D inhibits the proliferation of T-cells by blocking mitosis and IL-2 production (26, 27), limits the differentiation of Th1/Th17 cells, which favors Th2 differentiation (–32), and induces the generation of IL-10 secretory Treg cells (–34). Additionally, T-cell proliferation is significantly reduced when DCs are exposed to 1,25(OH)₂D₃ (16). T-cell cytokines also regulate VitD metabolism by monocytes. Thus, the Th1 cytokine IFN-γ induces CYP27B1, leading to the conversion of 25(OH)D to 1,25(OH)₂D, whereas the Th2 cytokine IL-4 promotes upregulation of CYP24A1 (35). Stimulation of B-cells with 1,25(OH)₂D leads to apoptosis, impaired plasma cell differentiation, decreased antibody production, inhibition of memory B-cell formation, and increased production of IL-10 (, –41).