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7. Vitamin D and HIV Infection


Joan Fibla1 and Antonio Caruz2.
1
Human Genetics Unit, Department of Basic Medical Sciences. Universitat de Lleida.
IRB-LLEIDA. Montserrat Roig, 2 25199-Lleida, Catalonia, Spain.
joan.fibla@cmb.udl.cat
2
Immunogenetics Unit, Faculty of Sciences, Universidad de Jaén, Pasaje Las
Lagunillas s/n 23071-Jaén, Spain. caruz@ujaen.es

Address correspondence to : joan.fibla@cmb.udl.cat

Abstract: Among environmental factors related to pathogen infection vitamin D


has been largely considered protective and promoter of good health. For this reason,
a general concern exists about vitamin D insufficiency that has been found around
world reaching epidemic dimensions. In the last few years, interest about vitamin D
role on immune response has been increased after encouraging data illustrating the
already well-known contribution of the binomial sunlight exposure/vitamin D on
protection to mycobacterium infections. The vitamin D mediated induction of
microbicide factors against bacterial infections runs in parallel with the vitamin D
immunosuppressant activity induced to control the exacerbation of the cellular
immune response. These complementary effects can be modulated to guarantee a
correct vitamin D action. Concerning to HIV infection a protective role can be
expected from the vitamin D mediated microbicide activity, but no single effects
can be deduced from the vitamin D immunosuppressant activity. In addition, the
direct effects of vitamin D by promoting HIV replication can act as a confounding
factor when trying to understand the role of vitamin D in HIV infection. In the
present review we have evaluated public available bibliography of vitamin D action
on the immune system response crossing them with data on HIV immunopathology
trying to find common pathways that can help us to a better understanding of the
role of vitamin D on HIV infection and disease progression to AIDS.

1. INTRODUCTION. In addition to its action by interacting with the nuclear


role on mineral metabolism, vitamin D receptor, vitamin D receptor (VDR), that
has pleiotropic effects on the control of acts as a transcription factor activating or
cell proliferation and on the modulation repressing specific genes [5].
of immune response [1-3]. Following the Although the immunomodulatory
activation of vitamin D precursors in the response triggered by active vitamin D
skin by the exposure to sunlight and their was first reported more than 25 years ago,
biochemical transformation in the liver, a growing body of experimental evidence
vitamin D acquires full active form after has been obtained in the last decade that
been converted to 1-Į-25- supports for a key role of vitamin D in the
dihydroxyvitamin D3 (1,25(OH)2D3) by control of both innate and acquired
the kidney enzyme 25-hydroxyvitamin immune response [6-8]. Both CYP27B1
D3 1-Į-hydroxylase (CYP27B1) [4]. At and VDR are expressed by several
the molecular level vitamin D excerpt its immune cells, such as macrophages
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(MAC), dendritic cells (DC) and pathways that can help us to a better
lymphocytes. This allows to these cells to understanding of the role of vitamin D on
synthesize and response to vitamin D in HIV infection and disease progression to
an autocrine/paracrine circuit involved in AIDS.
the modulation of the immune response
[6]. The active vitamin D hormone 2. VITAMIN D SOURCES AND
stimulates the innate immune response in ENDOGENOUS SYNTHESIS. Vitamin
MAC and DC, while at the same time acts D is a seco-steroid hormone that has
to squelch any overzealous reaction in the pleiotropic effects on the regulation of
adaptive immune response to the antigen. mineral metabolism and the modulation
These contrasting effects confer to the of the immune response [1,2]. Sources of
vitamin D endocrine system a central role vitamin D come from dietary intake of
in the modulation of the immune foods that are rich on vitamin D, mainly
response, being responsible of a proper fish liver oils and egg yolks, and from
and well-dimensioned response. endogenous synthesis by photolysis
In the present review we have emphasised reaction in the skin (Figure 1). There are
on the involvement of vitamin D on two main forms of vitamin D used by the
infectious diseases, and specifically on human body, vitamin D2 and vitamin D3,
HIV infection and disease progression to which have a chemical structure closely
AIDS. A potential role of vitamin D on related to the cholesterol molecule.
HIV infection has been previously Ultraviolet radiation (UVB), at the 290-
considered; indirectly through sun light 315 nm wavelength ranges, alter the
exposure [9] or taking into consideration cholesterol-based precursor 7-
the prevalence of vitamin D insufficiency dehydrocholesterol in human skin by
in HIV infected patients [10-14]. A breaking C-9 and C-10 of the B ring to
growing body of evidence supports for a form the pre-vitamin D3. Following this,
role of vitamin D as protection factor in naturally occurring thermogenic
intracellular pathogen infection, such as isomerisation forms the unhydroxylated
mycobacterium, through activation of vitamin D3 form cholecalciferol (calciol)
innate immune response [15], despite that is biologically inactive. In a similar
vitamin D has been found detrimental in way, vitamin D2 is formed from the
Leishmania infection by interfering key irradiation of ergosterol, a plant sterol
functions of interferon (IFN)-Ȗ activated that can be ingested within the diet.
macrophages [16]. In addition, direct Endogenously produced vitamin D3 can
effects of vitamin D promoting HIV be selectively transported in the
replication has been described [17,18] bloodstream by vitamin D binding protein
and association studies of VDR gene (DBP) to target cells of the vitamin D
polymorphism seems to indicate that gene endocrine system for metabolism. In
variants that hamper VDR mediated addition, vitamin D3 supplied by the diet
activity are associated with susceptibility can be adsorbed through the duodenum
to infection and disease progression to and transported into lymph via
AIDS [19- 22]. chylomicrons.
In the present review we have evaluated To reach its active form vitamin D3
public available bibliography of vitamin undergoes two sequential hydroxylations.
D action on the immune system response First, in the liver, vitamin D3 is
crossing them with data on HIV enzymaticaly hydroxylated to the C-25
immunopathology trying to find common group by the monooxygenase activity,
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Figure 1. Vitamin D synthesis. Ultraviolet radiation acts on 7-dehydrocholesterol in


human skin to form the pre-vitamin D3, that after thermogenic isomerisation forms
cholecalciferol (calciol). In addition, vitamin D2 and vitamin D3 can be supplied by the
diet. Active vitamin D3 is formed by two sequential hydroxylation in the liver and kidney,
to produce 25(OH)D3 (calcidiol) and 1,25(OH)2D3 (calcitriol), respectively. In addition to
renal vitamin D synthesis, other tissues and cell types, such as keratinocytes, APC (MAC
and DC) and other immune system cells has the capability to produce active hormone.
Vitamin D produced in extra-renal tissues acts locally in a paracrine/autocrine manner and
usually do not contribute to the hormone levels in circulation.

mainly P450 cytocrome sterol 27- 1,25(OH)2D3 form is tightly regulated in


hydroxylase (CYP27A1), to produce the the kidney by parathyroid hormone
major circulating vitamin D form, 25- (PTH), calcium and phosphorus levels. In
hydroxycholecalciferol (25(OH)D3) also response to low calcium and elevated
known as calcidiol.This 25(OH)D3 is phosphorous, PTH is released by the
then transported to the kidney by DBP parathyroid gland to stimulate calcium
where it is further metabolised by the resorption and activate CYP27B1 to
hydroxylation of C-1. This key step is synthesize more 1,25(OH)2D3 that helps
performed in the proximal tubular cells of on this way. Over production of
the nephron by P450 cytocrome 25- 1,25(OH)2D3 is regulated by a negative
hydroxyvitamin D3 1-Į-hydroxylase feedback loop by which 1,25(OH)2D3
(CYP27B1) enzyme to produce inhibits PTH synthesis and induces 1,25-
(1,25(OH)2D3), also known as calcitriol, dihydroxyvitamin D3 24-hydroxylase
that corresponds to the “active” or (CYP24A1) activity in a very sensitive
“hormonal” form of vitamin D. This manner [24]. CYP24A1 participates in
hormonal form of vitamin D plays an the 1,25(OH)2D3 catabolism by
essential role in stimulating intestinal incorporating a hydroxyl group on C-24
absorption of calcium and phosphorus, in allowing its excretion in the bile.
the mobilization of calcium from bone, In addition to renal vitamin D synthesis,
and in renal resorption of calcium [23]. other tissues and cell types has the
While the liver conversion of vitamin D3 capability to convert 25(OH)D3 to the
to 25(OH)D3 is not actively regulated, the active 1,25(OH)2D3 form. This
conversion of 25(OH)D3 to the active conversion is due to the activity of
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CYP27B1, the same enzyme that is form [32]. This autonomous vitamin D3
present in the kidney. Extra-renal pathway has been also reported in
synthesis was first reported on studies of intestinal CaCo-2 and myeloid THP-1
granulomatous diseases such as cell lines [33]. Recently, it has been
sarcoidosis, characterised by an ectopic described that also human primary MAC
over production of 1,25(OH)2D3. Primary and DC are able to perform both
cultures of pulmonary alveolar MAC of hydroxylation steps on vitamin D3
patients with sarcoidosis showed a precursor, allowing them to develop an
significant level of conversion of autonomous production of active vitamin
25(OH)D3 to 1,25(OH)2D3, but, in D [34].
contrast to renal conversion, macrophage This autonomous production of the
CYP27B1 activity did not respond to the hormone could be of vital importance in
1,25(OH)2D3 dependent negative tissues with limited availability of both
regulation, being sensitive to up- 25(OH)D3 and 1,25(OH)2D3. To reach
regulation by IFN-Ȗ [25]. This explains keratinocytes in deeper layers of the
the observed overproduction of epidermis 25(OH)D3-carrier complexes
1,25(OH)2D3 and the associated must cross from low vascularised
hypercalcemia that characterizes severe stratums. Under these circumstances the
forms of this disease, besides indicate a low concentration of 25(OH)D3 could
distinct regulation for the extra-renal impair enough synthesis of the functional
enzyme. Extra-renal sites for CYP27B1 hormone. Total serum concentrations of
expression include skin, endothelium, 1,25(OH)2D3 are in the range of 10-11 to
lymphoid organs, decidua, parathyroid, 10-10 M, being too low to induce
pancreas, adrenal medulla, colon and hormonal response on target cells, such as
cerebellum [26]. Expression of CYP27B1 skin keratinocytes in peripheral tissues
activity has been also described in normal [35]. Even more if we consider that near
MAC [27] and other antigen presenting 99% of serum calcitriol is bound to
cells such as DC [28] and Langerhan cell carrier, which means that less than 1% of
(LC) [29]. In addition, T lymphocytes serum calcitriol, corresponding to a
obtained by bronchoalveolar lavage of “functional” concentration of 10-13 M,
patients suffering granulomatous disease remains free and able to induce hormonal
such as tuberculosis [30] and T Cell response.
Lymphotrophic Virus-I-transformed The autonomous capacity of
Lymphocytes [31] has been shown to keratinocytes to produce functional
produce 1,25(OH)2D3. The functional hormone from vitamin D3 precursor can
hormone produced in extra-renal target overcome this limitation. High levels of
tissues acts locally in a vtamin D precursors are present in the
paracrine/autocrine manner and usually skin coming from UVB photochemical
do not contribute to the hormone levels in activation, that could be incorporated in
circulation. the autonomous production of functional
Autonomous synthesis of vitamin D, from 1,25(OH)2D3 in keratinocytes, dermal
7-dehydrocholesterol to 1,25(OH)2D3, MAC and DC. In addition, ingested
can be achieved in the skin keratinocytes vitamin D precursors can serve as
as they can perform the sequential substrate for the autonomous production
hydroxylation at both C-25 on previtamin of functional 1,25(OH)2D3 in MAC and
D3 to be converted to 25(OH)D3 and C-1 DC from the gastrointestinal tract.
to transform it to the 1,25(OH)2D3 active
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Following this, the direct local conversion “classical“ nuclear VDR could act as the
of vitamin D precursors to functional membrane receptor being responsible for
hormone in the skin and the gut could the vitamin D rapid response [37]. Recent
overcome the limited access to the reports also proposed that an alternate
systemic hormone. This could be pocket conformation in the ligand-
essential for these two “barrier” systems binding domain of the nuclear VDR is
to enable an appropriate vitamin D involved in the rapid response [38]. A
dependent innate immune response. candidate for the rapid response-related
membrane binding protein/receptor for
3. GENOMIC AND RAPID 1,25(OH)2D3 was isolated from chicken
RESPONSE PATHWAY TO intestinal basolateral membrane [39] and
VITAMIN D. Genomic and rapid also detected in mammalian cell
response pathways to vitamin D have membranes [40, 41], termed MARRS for
been described on target cells. While slow membrane-associated rapid-response to
response normally takes hours to days to steroid. The 1,25(OH)2D3-MARRS
reach full manifestation, being dependent protein has no sequence similarity with
on new protein synthesis, rapid response the nuclear VDR. Characterization of
to 1,25(OH)2D3 only needs seconds to chicken cloned MARRS cDNA sequence
minutes to become manifested, being reveals it to be identical to the
unaffected by inhibitors of transcription multifunctional protein ERp57, also
and translation. Genomic responses are known as Protein disulfide-isomerase A3
initiated following interaction between precursor (PDIA3) [40], a highly
the vitamin D compound and the nuclear conserved protein among several species.
VDR, whereas the rapid response ERp57/PDIA3/1,25D3-MARRS receptor
pathway has been related to a putative is member of the protein disulphide-
1,25(OH)2D3 membrane-associated rapid isomerase (PDI) family of
response steroid-binding protein oxidoreductases that contains two redox
(MARRS). domains. It works in a variety of cellular
processes as an essential protein in many
Evidences for a vitamin D membrane cell functions. PDIs are involved in native
receptor. The rapid-acting response have disulphide bond formation of
been observed in several contexts as fast glycoproteins in the endoplasmic
intestinal absorption of calcium, secretion reticulum (ER), acting as chaperone
of insulin by pancreatic cells, rapid proteins. PDIs participate in the antigen
migration of endothelial cells and presentation process facilitating the
aperture of Ca2+ and Cl- voltage-gated formation of disulphide bonds in the
channels in osteoclasts. This rapid and nascent MHC class I heavy chains
non-genomic related response seems to be [42,43] and the mentioned 1,25D3-
mediated by the activation of signal MARRS receptor function [44]. Besides
transduction pathways, including protein to the ER, PDIs are present on the cell
kinase C, cAMP, intracellular calcium surface, in plasma membrane rafts,
and MAP kinase [36] in target cells cytosol and nucleus [45]. The reducing
through a putative cell membrane- activity on disul¿de bonds mediated by
associated receptor for 1,25(OH)2D3. The the cell surface PDIs seems to be related
nature of the membrane receptor for with the infective capacity of certain
vitamin D has been extensively debated viruses, such as the Sindbis virus [46] and
with some authors arguing that the HIV [47]. Thiol-disulfide exchange
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reactions have been described to be sequence motifs acting as vitamin D


crucial during the penetration of cells by responsive elements (VDRE) composed
virus disrupting the rigid protein-protein of direct repeats of consensus
associations of the envelope and PuG(G/T)TCA motifs [49] that are
facilitating membrane fusion and release recognised by the 1,25(OH)2D3-VDR-
of the viral genome into the cell [46]. RXR complex. 1,25(OH)2D3-VDR-RXR
Antibodies against PDI and inhibitors of complex recognition to a VDRE
disulphide isomerase activity have been activating motif facilitates the assembly
described to interfere with virus-host of the transcription initiation complex by
membrane fusion. It has been proved that the release of corepressors and the
thiol-disulfide interchange mediate HIV- recruitment of basal transcription factors
target cell fusion. Reduction of critical and co-regulator molecules, including
disulfides in viral envelope glycoproteins members of the steroid receptor
may be the initial event that triggers coactivator (SRC) family and the VDR
conformational changes required for HIV activating proteins (DRIP) that modulates
entry [47]. Although, it has yet to be chromatin remodelling to increase RNA-
determined whether, and to what extent, polymerase II gene transcription rate.
these PDI mediated phenomena are Alternatively, when the ligand-VDR-
affected by the interaction with the RXR complex is engaged to an inhibitory
vitamin D endocrine system. VDRE, corepressors are recruited to
inhibit gene transcription.
Nuclear vitamin D receptor. Genomic In addition, VDRE independent
actions of the vitamin D on target cells regulation of gene transcription by
are mediated by the nuclear VDR, which 1,25(OH)2D3-VDR complex has been
belongs to the family of steroid-hormone described. By this way, 1,25(OH)2D3
receptors [48]. Full length VDR protein excerpts regulatory role by interfering
has a molecular weight of 48 kDa that with the signal of key immune related
shows nuclear localization motif and transcription factors such as activating
several functional domains such as protein-1 (AP-1), nuclear factor of
ligand-binding domain to the hormone, activated T-cell (NFAT), specific protein-
DNA-binding domain that binds to the 1 (Sp1) and nuclear factor kappa-light-
vitamin D response elements (VDREs) chain-enhancer (NF-țȕҗ transcription
located in the promoter region of target factor) of activated B cells. The
genes, dimerization domain with allows biological actions resulting from
its binding with partner retinoic X 1,25(OH)2D3-VDR transcriptional
receptor and transactivation domain that regulation have pleiotropic effects
mediates transcriptional activation affecting genes involved on the vitamin D
(Figure 2). hormone synthesis/catabolism and
Interaction of 1,25(OH)2D3 with VDR calcium homeostasis [50], cell
induces translocation from the cytosol to differentiation and suppression of cell
the nucleus, where it heterodimerizes proliferation [51], neuroprotection in the
with its partner retinoic X receptor central nervous system [52] and
(RXR), to form a protein complex that modulation of innate and adaptative
acts as a transcription factor involved in immune response [53].
the regulation of transcriptional activity Human VDR gene expands over 100 kb
of target genes. Promoter region of of the chromosome 12q13.11 and consists
vitamin D responsive genes shows of 14 exons distributed among 5’UTR
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Figure 2. Schematic structure of the vitamin D receptor protein.VDR protein shows


several functional domains. Nuclear localization motifs and DNA binding domain with two
zinc fingers motifs are located at the N-terminal region. Hormone-binding domain is
extended along C-terminal half of the molecule including the activation function (AF)-2
domain on the C-terminal extreme. Scattered regions define the heterodimerization domain
that allows binding with partner retinoic X receptor.

region (upstream exons 1a to 1e), protein 1,25(OH)2D3-VDR mediated


coding region (exons 2 to 9) and 3’UTR activation/repression of immune genes
region (exon 9) (Figure 3). VDR gene can be done in a VDRE dependent and
expression is under complex independent manner (Table 1). Increase
transcriptional control by multiple of tumour necrosis factor (TNF)-ҟĮ
promoters. Distal promoter (1f) and production on 1,25(OH)2D3 treated bone
proximal promoters (1a and 1d) generates marrow cells is mediated by direct
multiple variant VDR transcripts showing binding of 1,25(OH)2D3-VDR-RXR
tissue and cell type specificity [54]. complex with VDRE in the TNF-Į
Naturally occurring mutations of VDR promoter [57]. Moreover, in peripheral
gene are responsible for the hereditary blood mononuclear cells of normal and
1,25(OH)2D3 dependent rickets (vitamin haemodialysis patients [58], in murine
D dependent rickets type II; VDDR II), MAC cell line P388D1 [59] and in
that is characterised by defective bone peritoneal MAC of patients treated by
mineralization, low intestinal calcium continuous ambulatory peritoneal dialysis
absorption, hypocalcaemia and elevated [60], 1,25(OH)2D3 has a potent inhibitory
serum levels of 1,25(OH)2D3. VDDR II effect on the production of TNF-Į. The
related VDR mutations are all inactivating inhibitory effect on TNF-Į production
mutations disturbing VDR DNA binding appears to be an indirect effect of both,
ability as well as transcriptional 1,25(OH)2D3–dependent reduction of
transactivation. VDR knockout mice have nuclear translocation of nuclear factor
been obtained that constitutes an animal kappa-light-chain-enhancer of activated B
model for the VDDR II [55,56]. cells (NF-țȕҗ transcription factor) [59] and
1,25(OH)2D3–mediated down-regulation
1,25(OH)2D3-VDR mediated of TLR2 and TLR4 [61].
transcriptional regulation of immune VDRE has been recently found in the
related genes. As for others promoter region of both the human
1,25(OH)2D3-VDR target genes, cathelicidin antimicrobial peptide
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Figure 3. Genomic architecture of the human VDR gene. A, Exon-intron structure of


VDR gene with non-coding (grey coloured) and coding (blue coloured) exons numbered
according [54]. B, VDR gene expression is under complex transcriptional control by
multiple promoters. Distal promoter (1f) and proximal promoters (1a and 1d) generates
multiple variant VDR transcripts showing tissue and cell type specificity [54]. Transcript
variant 1 (VDR.1) lacks an alternate exon in the 5' UTR (1b) compared to variant 2
(VDR.2). Variants 1 and 2 encode the same protein. Additional rare variants have been
described using alternate promoters, at 1f and 1d, and alternative splicing rendering VDR
isoforms [54].

(CAMP) gene and the defensin-ȕ2 (defȕ2) Down regulation of interleukin (IL)-12
gene, mediating 1,25(OH)2D3 and IL-8 is mediated by ligand-VDR
antimicrobial peptide induction in complex that impedes both the activation
monocytes, MAC and keratinocytes [49, of NF-țȕ transcription factor and the
62]. Negative VDRE-mediated response binding to the NF-țȕ consensus motif in
has also been described for the the promoter sequence of these two
1,25(OH)2D3-mediated inhibition of IFN- genes. Moreover, 1,25(OH)2D3 also
Ȗ [63] and granulocyte MAC colony- influences the activity of NF-țȕ by
stimulating factor (GM-CSF) production interfering i) the ubiquitination and
[64]. In addition, 1,25(OH)2D3-VDR also subsequent degradation of the cytosolic
mediates VDRE independent regulation inhibitor of NF-țȕ (IțȕĮ) and ii) by
of gene transcription, through a direct or inhibiting NF-țȕ nuclear translocation
indirect influence on signalling cascades. and DNA binding. 1,25(OH)2D3 can also
By this way, 1,25(OH)2D3-VDR complex regulate transcription of NF-țȕ genes
can interfere, in a dose-dependent such as RelB and c-Rel. A negative
manner, with the signalling of key VDRE has been described in the
transcription factors involved on the promoter region of RelB gene that is
regulation of immune related genes. NF- constitutively linked to unbound VDR.
țȕ is a major transcription factor that This VDR-promoter association is
regulates genes responsible for both the enhanced by ligand-binding but reduced
innate and adaptive immune response. by LPS[65].
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Table 1. 1,25(OH)2D3-VDR mediated transcriptional regulation of immune related


genes.
Regulatory Target gene Action mechanism and effect on gene Refs
mechanism transcription
VDRE mediated regulation
Activating TNF-Į Direct interaction of ligand-VDR-RXR [49,57]
VDRE Cathelicidin with VDRE. Increase transcription
Defensin-ȕ2
GM-CSF Direct binding of ligand-VDR [64]
monomers to VDRE. Increase
transcription
Repressing IFN-Ȗ Direct binding of ligand-VDR-RXR [63]
VDRE with VDRE and inhibition of an
upstream enhancer element. Inhibition
of transcription
RelB Constitutive binding with unliganded- [65]
VDR that is increased by ligand and
decreased by LPS. Inhibition of
transcription
Non VDRE mediated regulation
NFkB pathway IL12p40 Indirect inhibition of NF-țȕ [66,67]
IL-8 heterodimer binding to promoter motif.
Inhibition of transcription
TNF-Į Reducing nuclear translocation of NF- [59]
țȕ. Inhibition of transcription
NFATp/AP1 IL-2 Interfering with NFATp/AP-1 complex [68]
pathway IL-4 assembly. Inhibition of transcription
MAPK pathway FasL Indirect inhibition of c-myc-mediated [69]
transcriptional activity. Inhibition of
transcription
SP-1 CD14 VDR/SP-1 interaction at promoter SP-1 [70]
transcription binding site. Increase transcription
factor

Thus, enhanced repression of RelB 4. VITAMIN D ROLE ON THE


transcription by 1,25(OH)2D3-VDR IMMUNE RESPONSE. Expression and
contributes to downregulation of the NF- regulatory properties of key components
țȕ pathway. In the same way, additional of vitamin D endocrine system,
pathways mediated by transcription CYP27A1, CYP27B1, CYP24A1 and
factors, such as NFAT/AP-1 and MAPK, VDR, on immune cells strongly supports
are involved on the 1,25(OH)2D3-VDR for a role of vitamin D on immune system
mediated inhibition of IL-2, IL-4 and Fas modulation. Since the first description of
ligand (FasL) genes, 1,25(OH)2D3/VDR metabolism acting in
whereas 1,25(OH)2D3-VDR/SP-1 may peripheral mononuclear leukocytes and
mediate CD14 upregulation (Table 1). MAC of healthy humans and sarcoidosis
189

patients [25,71], vitamin D action on Vitamin D action on innate immune


immune system has been mainly response.
considered in the context of both The main features of vitamin D effect on
immunosuppressive activity on APC and immune system regulation are depicted in
immunomodulatory effect on Th Figure 5 and Table 2. On the first steps of
lymphocyte polarization. Recently, the infection pathogen access to body by
involvement of vitamin D endocrine crossing physical obstacles such as
system on the induction of innate immune epithelial barrier to reach contact with the
response offers a new and promising internal environment of the host. MAC,
picture from which the role of vitamin D DCs and LCs are the first immune cells
on immune system regulation emerges that interact with pathogens. This
with contrasting and pleiotropic effects. interaction is performed by the
recognition of pathogen products, so
Regulation of vitamin D endocrine system called pathogen-associated molecular
on immune cells. VDR is expressed in patterns (PAMPs), by a subclass of
most cell types of the immune system pattern recognition receptors (PRRs)
[71,72], in particular APCs such as MAC, located in the plasma membrane of these
DCs [73] and LCs [74,75], as well as in cells. Among membrane-bound PRRs are
CD4+ and CD8+ T cells [72]. the transmembrane proteins known as
Constitutive expression of VDR has been Toll-like receptors (TLRs) that have the
observed in MAC and DCs whereas their capability to recognize a broadly varying
expression is induced by immune type of molecules, including peptides,
stimulus in B and T lymphocytes. lipids and nucleic acids [78]. These
Regulation of VDR expression in APC interactions result in triggering
(monocyte/MAC and DC) depends on downstream signalling cascades, many of
maturation status. which terminate in the activation of
Immature APC express basal levels of transcription factor NF-țȕ. The final
VDR that allow their responsiveness to result is the induction of the innate
agonist stimulus. When infectious agent immunity as well as the instruction of the
interacts with DC and MAC these cells adaptive immune response against
mature to capture and present antigens. pathogen. Mainly, innate immune
Maturation process is characterised by the response is conducted in the form of
upregulation of CYP27B1 expression and antigen phagocytosis and pathogen
the downregulation of VDR expression destruction as well as promotion of
(Figure 4). As a consequence, mature microbial killing by host antimicrobial
APC produce large amounts of peptides (AMPs). Following this,
1,25(OH)2D3 while loose their capability adaptive immune response is instructed
to respond to the hormone. As a result, a by the initiation of cell (cytotoxic activity
paracrine circuit is generated in which by T lymphocytes) and/or humoral
neighbouring immature APC respond to (antibody production by B lymphocytes)-
the hormone produced by mature APC directed immune response. Finely tuned
(Figure 4). Afterwards, 1,25(OH)2D3 mechanisms are running to avoid
produced by mature APC inhibits exacerbate innate and adaptive immunity
maturation switch of neighbouring in which vitamin D plays a key role.
immature cells contributing to suppress 1,25(OH)2D3 synthesis is upregulated in
immune activation [76,77]. response to TLRs activation, acting in an
autocrine/paracrine fashion to promote
190

Figure 4. Regulation of vitamin D receptor (VDR) and 25-hydroxyvitamin D3 1-Į-


hydroxylase (CYP27B1) synthesis during maturation of antigen presenting cells
(APC). APC, such as DC and MAC express basal levels of VDR that allow their
responsiveness to ligand stimulus. Activated monocyte (DC and MAC) become induced to
maturate (green lines). Maturation process is characterised by the upregulation of
CYP27B1 expression (green degraded lines) and the downregulation of VDR expression
(blue degraded lines). As a result, APC produce large amounts of 1,25(OH)2D3 while lost
their capability to respond to the hormone. Neighbouring immature APC can responds to
1,25(OH)2D3 secreted by mature APC, by inhibiting star of maturation through ligand-
VDR interaction (red lines). By this paracrine circuit 1,25(OH)2D3 can lead to the
suppression of further DC development.

APMs synthesis, such as cathelicidin and an autocrine feedback regulator of MAC


defensin-ȕ2, while at the same time, responses (Figure 5). 1,25(OH)2D3
keeping a check on the vigour of the mediates innate immune response against
adaptive immune response to pathogen Mycobacterium tuberculosis in MAC by
[79]. In this way, the capability of the induction of antimicrobial peptides
1,25(OH)2D3 to inhibit NF-țȕ pathway such as cathelicidin [15]. CYP27B1 and
and to suppress MAC TLR expression VDR genes are induced in MAC as a
supports for a key role of the hormone as response to infection by M. tuberculosis
191

Figure 5. Vitamin D action on innate and acquired immune response. Vitamin D


affects innate (right) and adaptive (left) immune response in a coordinated fashion.
Pathogen activated MAC TLR stimulates CYP27B1 synthesis (blue lines) to produce
increased amounts of 1,25(OH)2D3 from his 25(OH)D3 precursor (black lines).
1,25(OH)2D3, trough interaction with VDR, promotes synthesis of microbial killing soluble
factors, cathelicidin and defensin-ȕ2 (green lines). Afterwards, 1,25(OH)2D3 acts on a
paracrine mode to control exacerbated response on APC and T cells. In response to
pathogens TLR is also activated in APC that, in addition to activate CYP27B1 synthesis to
produce 1,25(OH)2D3, act through activation of NF-țȕ to promote antigen presentation and
Th1 polarization (blue lines). 1,25(OH)2D3 produced by MAC and APCs inhibits NF-țȕ
pathway (red line) modulating APC response. In addition, 1,25(OH)2D3 inhibited the
polarization of Th0 cells to Th1 profile by inhibiting the production of Th1-promoting IL12
from APC and B cells and down regulating Th1 specific cytokines (IL-2 and IFN-Ȗ) (red
lines). Finally, locally produced 1,25(OH)2D3 acts on Th0 cells by promoting Th2 and Treg
polarization, in B cells by inhibiting immunoglobulin (Ig) G and activating IgE production
and in MAC by inhibiting TNF-Į production. A control on the innate immune response is
also assumed by 1,25(OH)2D3 by inhibiting TLR synthesis that contributes to shut off the
immune response circuit. Worse 1,25(OH)2D3 synthesis can be produced as no feedback
control on CYP27B1 activity exist. In addition, 1,25(OH)2D3-catabolism is impaired in
MAC. Non-functional mRNA splice variant, CYP24A1-SV, interfers with normal
CYP24A1 enzyme attenuating 24-hydroxylase-enzyme activity, which strongly reduces the
conversion of active hormone to their catabolic products.
192

through the AP-1/NF-țȕ pathway. induction of the innate immune response


induced after TLR2/4 bacterial activation. as well as for the instruction of the
Following this, hydroxylation of adaptive immune response against
25(OH)D3 to 1,25(OH)2D3 produces pathogens [102]. Although, an extensive
large amounts of active vitamin D release of TLR-triggered pro-
hormone that, after interaction with VDR, inflammatory mediators can be capable of
can modulate the expression of vitamin D harming the host, as comes clinically
dependent genes. Among these, the overt in cases of sepsis or autoimmune
defensin-like cathelicidin gene is disorders [61]. It has been proposed that
upregulated through the interaction with 1,25(OH)2D3 produced by TLR
the VDRE enhancer located on its stimulated MAC or endogenously
promoter [98]. There is no feedback produced 1,25(OH)2D3 by APC protects
control for the induced 1,25(OH)2D3 from exacerbated TLR signalling by
production in MAC, whereas in other down-regulation of pro-inflammatory
cells the negative feedback mediated by cytokines (INF-Ȗ ҏand TNF-Į), antigen-
the 1,25(OH)2D3-cathabolic enzyme presenting and costimulatory CD40,
CYP24A1. While CYP24A1 expression CD80/86 molecules, and, most
is also induced in MAC with CYP27B1 importantly, down-regulation of TLR in
and VDR genes, there is no concomitant MAC and APC [61].
increase in 24-hydroxylase-enzyme
activity. It has been shown that CYP24A1 Vitamin D action on T-lymphocyte
expression in MAC produces, in addition polarization. The contribution of
to the normal CYP24A1 mRNA, an 1,25(OH)2D3/VDR on the modulation of
mRNA splice variant, CYP24A1-SV, that immune response is also emphasised by
in the translated product lacks the its role on T-lymphocyte polarization
mitochondrial targeting domain [101]. (Figure 5).
It has been proposed that CYP24A1-SV Although 1,25(OH)2D3 can act directly
interferes with normal CYP24A1 enzyme on T cell function, the main
attenuating 24-hydroxylase-enzyme immunomodulatory effects on T cell
activity, which strongly reduces the differentiation is done indirectly, through
conversion of active hormone to their their action on APC.
catabolic products. Naïve CD4+ T helper (Th) cells, upon
Activation of TLR initiates protective stimulation by specific antigen, can
immune responses with both innate and differentiate into pluripotent Th0 cells
adaptive profile. Thus, the that produce a broad pattern of cytokines.
aforementioned induction of Under the influence of specific
1,25(OH)2D3/VDR-mediated AMPs stimulatory soluble factors and
production by MAC goes together with costimulatory molecules expressed by
the TLR-mediated activation of NF-țȕ APCs, pluripotent Th0 cells further
transcription factor pathway in APCs differentiate into Th1, Th2 and T
resulting in the release of regulatory (Treg) cells that express a
proinÀammatory cytokines and limited and specific number of cytokines.
chemokines as well as the upregulation of Th1 subset is characterised by the
co-stimulatory molecules that are expression of the pro-inflammatory
essential for T-cell activation (Figure 5). cytokines IL-2 and IFN-Ȗ. The secretion
Then, activation of TLR signalling of IL-4, IL-5 and IL-10 cytokines
pathway is a critical element for the distinguishes Th2 subset.
193

Table 2. Vitamin D action on target immune cells.


Target Effects of processes and product cells
Inhibits Induces/Favours
T cells
T cell proliferation >80@ Hyporesponsiveness to self
antigens >81, 82@
Th1 polarization >83, 84@ Th2 polarization >83@
NF-kB activation >85@ T-regulatory cells >86@
IL-2 and IFN-J>63, 66@ CD95 (FasR) >69@
GM-CSF >87@ CD152 (CTLA4) >81@
GATA-3 >88@
IL-4, IL-5, IL-10 >81@
Dendritic cells
Differentiation, maturation >89@ Apoptosis >81@
IL-12 >66@ IL-10 >81@
TNF-D (mature DC) >61@ TNF-D (immature DC) >57@
MHC II mediated antigen presentation >90, Tolerogenic status of myeloid
91@ DC >92, 93@
Costimulatory molecules CD14 >91@
(CD40, CD40L, CD80, CD80L) >94@
DC migration >95@
MAC/Monocyte
Effector function of IFN-J-activated MAC: Chemotactic and phagocytic
Listericidal activity and phagocyte oxidase- capacities >92@
mediated burst >96@
Costimulatory molecules Cathelicidin >49, 98@
(CD40, CD40L, CD80, CD80L) >97@
TLR2/4 expression >61@ Defensin-E2 >49@
TNF-D (in mature cells) >58, 99@ TNF-D (in immature cells) >57@
NF-kB activation >59@ CD14 >57@
B cells
Proliferation of activated B cells >100@ Apoptosis >100@
Ig production >100@
Cell cycle progression >100@
Memory B cell differentiation >100@

Finally, a third subset of T cells may be APC secreting IL-12 and presenting
induced, such as Treg cells, characterized MHC II-coupled antigens and co-
by the secretion of IL-10 and TGF-ȕҏ stimulatory molecules.
[103]. The decision by which Th0 cells Antigen presentation by APC in the
undergoes differentiation to one of these absence of IL-12 stimulus promotes Th2
T cell subsets depends on multiples differentiation.
factors from which APC driven stimulus Finally, APC lacking co-stimulatory
are crucial. Th1 pro-inflammatory molecules become tolerogenic and, in the
response is promoted in the presence of presence of IL-10, give rise to regulatory
194

T cells or even induces T cell anergy response, ii) the detrimental effect of Th1
[104]. Both Th2 and Treg cells inhibit inhibition and iii) induction of a
Th1 differentiation, reason why Th1 tolerogenic status has to be considered for
profile is prevented if Th2 or Treg has each disease model. The suppressive
been induced. Th1/Th2 balance effects of 1,25(OH)2D3/VDR pathway on
hypothesis has been proposed by which MAC functions have been revealed
each T-helper subsets directs different detrimental in certain infection models
immune response pathways. Type 1 such as Leishmania major infection. In
pathway is directed by Th1 cells and is this intracellular protozoan parasite
mainly involved in intracellular microbe infection, host defence is focused around
control and cellular mediated immunity. activated MAC acting as IFN-Ȗ-effector
Th2 cells drive type 2 pathway, being cells.
involved in the control of extracellular Given the suppressive effect of
parasites and in humoral mediated 1,25(OH)2D3/VDR on Th1-mediated
immunity. Although criticised by some IFN-Ȗ production a detrimental role for
authors, Th1/Th2 balance hypothesis has 1,25(OH)2D3 can be expected. In line
been considered as a paradigm on co- with this, MAC of VDR-knock-out
ordinating immune response. Unbalanced (VDR-KO) mice has stronger
Th1/Th2 response predisposes to immune leishmanicidal activity that is reduced
diseases. Dominance of Th1 drive when exposed to 1,25(OH)2D3,
response has been associated with supporting a negative role of the hormone
autoimmunity, whereas, Th2 over- [16].
dominance has been related with allergy Analogous results was observed in the
[103]. 1,25(OH)2D3/VDR action on APC mouse model of AIDS (LP-BM5 murine
is characterised by the down-regulation of leukemia virus); treatment with 1,25-
the expression of the co-stimulatory (OH)2D3 enhanced the severity of the
molecules CD40, CD80 and CD86, disease and increases the mortality rate
reduction of IL-12 and augmentation of [106].
IL-10 production. This resulted in a Concerning to HIV-1 infection, evidences
decreased T-cell activation that creates an exist indicating that HIV-1-specific
environment that favours Th2 and, cellular immune responses may play a
mostly, Treg differentiation [84,86,94, critical role in antiviral control [107]. Th1
105]. Inhibition of Th1 response and mediated immune response seems to be
promotion of Th2 and Treg differentiation poorly developed in HIV-1 infected
has been related with 1,25(OH)2D3- patients at all stages of the disease.
mediated protection against autoimmune In addition, T-cell proliferative responses
diseases [84]. In addition, 1,25(OH)2D3- against virus are inversely correlated with
promoted tolerogenic status substantiate plasma viremia [107].
its therapeutic use to prevent allograph Importantly, in many seronegative
rejection [92]. exposed individuals and long-term non-
progressors a vigorous HIV-1 specific
Vitamin D effect on host Th1 mediated Th1 and cytotoxic T-lymphocytes (CTL)
immunity against intracellular pathogens. response has been observed [108].
In the context of infection by intracellular Several authors have proposed a shift
pathogens, the balance between i) from Th1 to Th2 immune response that
positive effects of the 1,25(OH)2D3/VDR correlates with HIV-1 disease progression
pathway by inducing anti-microbial [109, 110]. Whatever this Th1>Th2 shift
195

constitutes a viral immune evasion infection, can be detrimental by limiting


strategy [111], it is favoured by the capability of MAC function to
opportunistic infections [112] or derived suppress intracellular grow of
from a selection process against more tuberculosis bacterium and compromising
permissive Th cells [113], the main the production of microbe-killing
consequence is that this Th1/Th2 cathelicidin [15].
imbalance could preclude to mount
humoral and cellular HIV-1 speci¿c Seasonal variation of sunlight exposure,
immune responses able to control virus vitamin D and immune function. Changes
infection. According to this, the in immunological parameters have been
1,25(OH)2D3-mediated Th1->Th2 shift described in tourist travelling to sunny
could have detrimental effects on both, countries without prior adaptation to
HIV-1 infection and disease progression UVB exposure. Subjects receiving
to AIDS. substantial doses of UVB, as reflected by
response to questionnaires, UVB
5. ENVIROMENTAL-MEDIATED dosimetry and increase in 25-
AVAILABILITY OF VITAMIN D hydroxyvitamin D3 show significant
AND IMMUNE FUNCTION. The alterations in the immune system function
association of abnormal status or [118]. A fashion hypothesis proposes a
environmental-limiting availability of link between sunlight exposure, vitamin
vitamin D hormone with several disease D availability and susceptibility to
conditions sustains the critical role of bacterial and virus infection. Following
1,25(OH)2D3/VDR pathway in normal this hypothesis, low sun exposure, due to
immune system function. In this way, limiting environmental conditions or in-
vitamin D deficiency, that tends to induce house social behaviour, predispose to
an over-grounded Th1 response, has been vitamin D insufficiency that could favour
associated with susceptibility to the acquisition of bacterial and viral
autoimmune diseases such as rheumatoid infections. In line with this hypothesis
arthritis, type-1 diabetes, systemic lupus prevalence of tuberculosis infection has
erythematosus, psoriasis, inflammatory been found higher in Asiatic immigrants
bowel disease and multiple sclerosis living in United Kingdom than in those
[114]. On the other hand, the over- living in their countries. From such a
induction of 1,25(OH)2D3/VDR pathway hypothesis, lowering the availability to
that precludes an accurate control of Th1 sunlight in northern latitudes can preclude
response and favour a Th2 response and a enough vitamin D synthesis, which
tolerogenic state, seems to predispose to predisposes Asian immigrants in the UK
allergic conditions [115,116]. Concerning to tuberculosis infection [119]. Also, the
1,25 (OH) 2D3 involvements on seasonal variation of influenza infection
susceptibility to pathogen infection, has been linked to the seasonal variation
evidence exist that vitamin D of sunlight exposure-related vitamin D
insufficiency predisposes to bacterial and deficiency [120]. However, the effect of
viral infections [7]. Susceptibility to additional climatic conditions, such as
Mycobacterium infection has been largely humidity and temperature, as well as the
related with vitamin D deficiency [117]. detrimental effect of UV exposure on
Low levels of vitamin D compromise survival of viral particles, cannot be rule
vitamin D-mediated immune modulations out [121]. A recent work evaluating
that, in the context of tuberculosis meteorological conditions in relation to
196

respiratory syncytial virus (RSV) in phototherapy and photo-chemotherapy,


infection reveals that RSV activity was on HIV-1 infected persons. Several
inversely related to UVB [122]. This studies have been addressed to clarify this
suggests that vitamin D insufficiency question that seems to discard any
during winter season increases adverse effects of UV radiation on HIV
susceptibility to respiratory infections and infected patients under UV phototherapy
imply that vitamin D supplementation can [126,127]. Immunosuppressive effects of
decrease their severity and occurrence. sunlight exposure have been also
Nevertheless, a recent report was not able considered detrimental in the context of
to detect any benefit of vitamin D HIV infection, being proposed as a risk
supplementation in decreasing incidence factor for progression to AIDS [9].
or severity of respiratory infections Epidemiological studies based on well-
during winter season [123]. Seasonal established HIV/AIDS cohorts have tried
variations in genital infections have been to address this question. Epidemiological
detected in cervical smears screened for data from the Multicenter AIDS Cohort
cervical carcinoma in the Netherlands Study (MACS) reveal that sunlight
[124]. Seasonal peaks for both Candida exposure is not associated with decline in
and Chlamydia were detected in fall T-helper lymphocyte count or progression
season. In contrast, infections of to AIDS [128]. Nevertheless, two studies
Actinomyces and Trichomonas were more based on the Amsterdam Cohort Study
likely in winter season. Concerning to (ACS) on HIV and AIDS shows
Human Papiloma Virus the seasonal peak contrasting results. The first study
was observed in summer season. evaluated individual exposure of
Complex interactions between host, homosexual men to sunlight by means of
infectious agent and environmental a 2-year retrospective questionnaire that
conditions can be taken into account to was given to some of the participants
explain this pattern of seasonality. The (n=57). In agreement with the previously
contribution of season-dependent mentioned study on MACS, exposure to
availability of vitamin D, if any, may be sunlight does not produce adverse effect
pathogen-specific. on CD4+ T-cell count, CD4+/CD8+ T
cell ratio, and T-cell reactivity [129]. The
Environmental-mediated availability of same authors developed a second study
vitamin D and HIV infection. There are by an extended number of subjects
few data relating sunlight and UVB (n=557) from which they found lower
exposure with HIV-1 infection that can levels in the mean number of CD4+ T
allow us to evaluate their impact on the cells and the mean CD4+/CD8+ ratio
disease. Early studies were interested on during summer and spring with seasonal
UVB effect on HIV-1 virus replication. effect being more prominent at a more
Transgenic mice expressing HIV Tat gene advanced stage of the HIV/AIDS [130].
under the control of the HIV LTR, The spread of HIV infection in Europe
showed bolstered Tat protein expression has been mainly due by injection drug use
in the skin after exposition to UV light (IDU) transmission. In the early HIV
[125]. If this effect was linked to UVB- epidemic the prevalence of the HIV
mediated vitamin D synthesis was not infection in IDU reach highest values in
investigated. Following these results, the Mediterranean area such as in Spain
concerns have been raised about potential (>60%), French (30%) and Italy (23-
adverse effects of UV radiation, as used 31%), as well as in North-Atlantic
197

countries such as Scotland (>64%) and factors excerpts the main effect on
Denmark (>20%) [131,132]. Social and prevalence. Later, we can expect a
political strategies for the prevention of plateau on prevalence, such as observed
HIV transmission among IDU were in western countries, in which “intrinsic”
implemented from the beginning of the factors determines the prevalence set
epidemic with encouraging results. As a point. The question we address is: what
consequence, a decrease in HIV are those “intrinsic” factors? Behavioural
prevalence was been observed in several and cultural singularities, that characterise
countries, but this reduction seems to each European region, could be critical,
have stabilised lower prevalence values in although, we can not exclude that
the Northern region than in Southern environmental factors such as sunlight
region [131,132]. Based on public data exposure/UVB radiation, and the
from surveillance of HIV/AIDS infection associated bolstering of HIV replication
in Europe [133] we have plotted in Figure and immunosuppressant effect, can be
6 the prevalence of HIV infection in IDU involved on the determination of the
subjects corresponding to selected prevalence set point. It is well known that
European country regions: Southern sensibility to the sunlight/UVB exposure
region with latitude <46ºN as for effects varies among human populations
Portugal, Spain and Italy, Central region depending on geographical location and
with latitude between 46ºN-55ºN as for skin colour. It is considered that
England, Germany and Austria and evolutionary forces acting on skin colour
Northern region with latitude >55ºN as variability in humans are strongly related
for Scotland, Norway and Finland. All with sunlight/UVB exposure [133].
these countries belong to the European Darker skin subjects are protected from
Union, except for Norway, and share sunburn and UVB-related damages, while
common political, economical and social they can have compromised vitamin D
characteristics. Prevalence trends in the metabolism, almost in high latitude
period 2001-2005 where highly stabilised regions. On the contrary, clear skin
for each region but larger values were subjects are vulnerable to sunburn and
observed in Southern (overall 15.3%) UVB-related damages, whereas they can
than in Central (2.0%) or Northern (0.6%) reach regular vitamin D metabolism,
regions. Taken into account that including in low irradiated regions.
prevalence of HIV infection in early It was stated that cutaneous photolysis of
epidemic was broadly extended in 7-dihydrocholestorol to cholecalciferol in
different European areas and that social the skin was strongly reduced in winter
and political strategies to prevent season in Boston (42ºN), while
infection has been applied with equivalent cholecalciferol production occurred
intensities among the states considered, it throughout the year in Los Angeles
is unexpected the differential set-point (34ºN) and San Juan de Puerto Rico
pattern achieved. Prevalence of HIV (18ºN) [134]. Calculation of the time
infection on eastern European countries is needed to reach enough amounts of
growing dramatically and no latitudinal vitamin D for a healthy vitamin D status
distribution can be observed. Probably, in has been modelled in the customizable
the early spread of the epidemic, such as web site
happened in the western European “http://nadir.nilu.no/~olaeng/fastrt/VitD_
countries in the eighteen's, quartMED.html” [135]. In the winter
socioeconomic, behavioural and political season (i.e. December) at 42ºN a subject
198

Figure 6. Prevalence of HIV infection among injection drug users in Southern, Centre
and Northern European regions. Mean prevalence of HIV infection in IDU subjects
corresponding to selected European country regions: South (latitude <46ºN; Portugal, Spain
and Italy) (blue line), Central (latitude 46ºN-55ºN; England, Germany and Austria) (red
line) and North (latitude >55ºN; Scotland, Norway and Finland) (black line). Data obtained
from public surveillance of HIV/AIDS infection in Europe [136] among 2002 to 2005
period. Prevalence trends in 2001-2005 for South Central and North regions were 15.3%,
2.0% and 0.6%, respectively.

with skin type 1 (Caucasian, very skin type VI, that need 2 hours and 13
sensitive, always burns easily, never tans, min in December and 16 min in July.
very fair skin tone) needs a minimum of Lightly coloured skin persons may likely
50 min to reach 1000 IU (daily access to any beneficial effect of vitamin
recommended dose). In contrast, a subject D production, while darker coloured
with skin type VI (dark-skinned black) persons will be protected from any
will need 24h of solar exposition to reach detrimental effect.
this minimal level. Values changed at the In an attempt to evaluate this proposition
summer season (i.e. July) in which we have searched in the literature for
subjects with skin type I and VI only need epidemiological studies evaluating
4 and 18 minutes, respectively, to reach prevalence of HIV infection on light and
the recommended minimal. At lower dark coloured people living at different
latitudes (i.e. 35ºN) the capability to latitudes. Unfortunately, there are not
synthesize functional vitamin D are not many studies of this nature from which
limited for people with skin type I, that we can extract information needed, but a
need 25 min in December and 3 minutes recent epidemiological study of HIV
in July, and lightly limiting for those with prevalence in civilian applicants for the
199

United States of America military service highly sunlight exposed and low
can help us in this way [137]. populated area, white people are more
This was an exhaustive analysis of the susceptible to infection than African-
geographical distribution of HIV American. We are conscious that any
infection throughout the US territory in conclusion derived from an exploratory
which they have studied 5,7 milions of analysis like this must to be taken with
subjects (79% White and 21% African- caution, but, at least we hope that this
American) who applied for US military could encourage the design of new
serive between 1985 and 2003. The epidemiological analysis trying to clarify
authors search for spatial HIV clustering this question.
of data, discriminating between White
and African-American clusters. They Vitamin D status and HIV infection.
found three main clusters for the White There is a great concern about vitamin D
data, one located in the Northeast area of status in the general population. Vitamin
New York and New Jersey, a second in D deficiency has been recognised as a
the Southeast area around Huston, Texas general problem with pandemic
and a third cluster in the Southwest area dimensions. Few foods contain enough
of Los Angeles, California (Figure 7). quantities of vitamin D and precursors,
Nevertheless, data from African- whereas cultural and social behaviour
American subjects reveals two stronger limit the access to photoproduction of
clusters in the Northeast area of New vitamin D precursors in the skin.
York-New Jersey and Washington DC Following this, synthesis of 25(OH)D3
and an additional cluster in the Southwest can be compromised limiting the
area of Los Angeles, but no cluster was synthesis of the 1,25(OH)2D3 active
detected in the Southeast area around form. It is well established that serum
Houston (Figure 7). It is remarkable that levels of 25(OH)D3 but not 1,25(OH)2D3
the two coincident cluster areas between are indicatives of the vitamin D status.
White and African-American correspond The circulating concentration of
to two of the most populated area in 25(OH)D3 is a good reflection of both
USA, whereas the discordant cluster exposure to sunlight and dietary intake of
corresponds to a more rural area. The vitamin D precursors. Although there is
high population density in these regions no a general consensus about the optimal
and the aggregation behaviour of human serum concentration of 25(OH)D3,
beings contribute to the spread of HIV vitamin D deficiency is considered when
infection among equals. We can interpret 25(OH)D3 serum levels are below 20 ng
that in highly populated areas, social, per millilitre (50 nmol per litre).
behavioural and economic factors However, other authors consider vitamin
overcome any additional factor affecting D insufficiency for serum concentrations
susceptibility to infection. When these between 20 to 30 ng per millilitre (50-75
factors are less prominent hidden factors nmol per litre) and sufficiency for values
can emerge. Then, environmental factors, greater than 30 ng millilitres.
such as sunlight exposure, could reveal Although occurring in rare circumstances,
their protective or detrimental effect on 25(OH)D3 can produce intoxication when
HIV infection in susceptible subjects. The serum levels are greater than 150 ng per
cluster detected in the Southern area millilitre (375 nmol per litre) [138].
around Houston, affecting only White
subjects, seems to indicate that, in a
200

Figure 7. Smoothed HIV prevalence and HIV clusters among white (A) and African-
American (B) civilian applicants for Unites States military service. Reproduced by
permission from Bautista CT, Sateren WB, Sanchez JL, Singer DE and Scott P. Geographic
mapping of HIV infection among civilian applicants for United States military service.
Health & place 2008;14:608-15 [137].

According to these definitions more than can affect vitamin D status. HIV infection
a million of people worldwide are has been recognised as a risk factor for
affected by deficient-insufficient status Vitamin D insufficiency. Deficiencies in
[139]. Among them, elderly, micronutrients were early described for
postmenopausal women and children are HIV/AIDS patients as a common feature,
the most significant risk groups. mainly in those with advanced disease
Environmental factors, sunlight exposure, [140].
latitude and season; nutritional factors, Abnormal levels of 1,25(OH)2D3 have
diet, fortified foods and dietary intake; been described in symptomatic HIV
behavioural factors, life style (i.e., indoor- infected patients (CDC stage IV) while
outdoor) and clothing; demographic near to normal levels were observed in
factors, age and finally, healthy factors those asymptomatic (CDC stage II/III).
201

Serum levels of the active hormone were Improvement of vitamin D status of HIV-
directly correlated with CD4+ cell counts infected patients by vitamin D
in blood and inversely correlated with supplementation has been studied in
survival. Although, 1,25(OH)2D3 levels several clinical trials, trying to improve
have been not correlated with vitamin D bone metabolism. Vitamin D
deficiency as determined by serum levels supplementation does not show side
of 25OHD3 [141,142]. Disturbances in effects on immune parameters as reflected
bone remodelling have been described in by the absence of significant changes of
patients with advanced disease, mainly CD4+ cell count and percentage of CD4+
related with increased activity of TNF-Į cells after one year of vitamin D
or direct HIV-effect on osteoblasts or supplementation [10,149]. On the other
osteoclasts precursors. As TNF-Į may side, on the same HIV individuals it was
inhibit 1,25(OH)2D3 effects on not possible to estimate the effect of
osteoblasts function [143], decreased vitamin D treatment on virus replication
levels of 1,25(OH)2D3 may act in a since all individuals were under anti-
synergistic way with increased TNF-Į retroviral therapy [10,149].
function by disturbing bone metabolism
in HIV infection [144]. 6. CONTRIBUTION OF VITAMIN D
Decreased activity of vitamin D ON PROTECTION/RISK TO HIV
metabolic enzymes has been described in INFECTION AND DISEASE
patients treated with protease inhibitors PROGRESSION TO AIDS. Both direct
(PI). PI inhibits enzymatic activity of 25- effects on HIV replication and indirect
and 1,25-hydroxylase enzyme (CYP27A1 effects through innate and adaptive
and CYP27B1, respectively) and, with a immunity responses affect the complex
less extends, 24-hydroxylase (CYP24A1) interactions of vitamin D endocrine
enzyme activity. In in vitro assays with system on HIV infection. Table 3
the human monocyte–MAC cell line summarises the contrasting effects of
THP-1 inhibition of 1,25–hydroxylase vitamin D on HIV infection that we
activity was of 80% by ritonavir, 66% by substantiate next.
indinavir and 32% by nelfinavir
[145,146]. Impaired vitamin D Vitamin D action on HIV replication may
metabolism during HAART regimens contribute to HIV infection. Conflicting
including PI may be responsible for the data have been reported concerning the
higher risk of bone dysfunction in effects of 1,25(OH)2D3 on HIV-1
patients under this treatment protocol replication in primary monocyte-derived
[147,148]. MAC as well as myeloid cell lines; both
The true relevance of vitamin D enhancement and inhibition of HIV-1
deficient/insufficient status in HIV replication in response to 1,25(OH)2D3
infected patients must to be considered in has been reported. Studies of the role of
the context of the general/healthy 1,25(OH)2D3 in HIV-1 infection have
population. been hampered by technical and
As stated in the epidemiological study methodological variability. Most of the
based on the Reaching for Excellence in studies lack homogeneity in the
Adolescent Health (REACH) cohort, the experimental strategies. Several
prevalence of vitamin D insufficiency in parameters can have deep influence on
HIV infected urban younger and control- the results: cell types, 1,25(OH)2D3
matched subjects were not different [12]. concentration, viral strains (X4 vs. R5),
202

1,25(OH)2D3 treatment before or after The main used models are cell lines of
infection, co-treatment with other stimuli myeloid origin, although several authors
(such as TNF-Į), chronic vs. acute have analyzed the 1,25(OH)2D3 effects
infection, days after infection for viral on primary cells.
load quantification or infectious dose.

Table 3. Contrasting effects of Vitamin D on HIV infection and progression to AIDS.

Vitamin D on HIV infection confers:

Protection by: Risk by:

Physiological Promoting polarization to Treg that Impairing Th1 cellular immune


evidences facilitates a proper modulation of response
the initial response

Promoting a tolerogenic status


that favour viral persistence

Inducing defensin synthesis Interfering in APOBECG3


synthesis

Increasing viral replication

Environmental Solar irradiation favours immune Lower levels of CD4+ T cells


evidences modulation and the mean CD4+/CD8+ ratio
in HIV+ patients during summer
and spring

High steady-state prevalence of


HIV infection in Southern
European countries

Genetic Less functional VDR-allelic


evidences variants that are associated with
protection to HIV infection and
slow progression to AIDS

HL-60 cell line was established from a phenotype after 1,25(OH)2D3 or phorbol
patient with promyelocytic leukemia. ester (TPA or PMA) stimulation. HL-60
This cell line acquires morphology and cells are CD4+/CXCR4+/CCR5- and
markers of mature granulocytes in the consequently are resistant to R5 but
presence of DMSO, retinoic acid, or susceptible to X4 HIV-1 strains [150].
cAMP and differentiates into a MAC-like However after 1,25(OH)2D3
203

differentiation (10-7 M) for 5 days, this replication; however, shorter


cell line becomes susceptible to HIV-1JR- 1,25(OH)2D3 stimulation reduced the
FL or HIV-1BaL (R5). In this study, the levels of viral replication and the
TPA also rendered the cells susceptible to simultaneous infection plus 1,25(OH)2D3
R5 viruses; this observation correlates treatment (10-8 M) produced a 75%
with the observed induction of CCR5 reduction in the viral load after 3 days of
after PMA treatment of HL-60 [151]. infection [157]. Skolnik et al. [158]
There was no effect of 1,25(OH)2D3 or reported 140-fold increase in viral
TPA on HIV-1JR-FL virus production from replication in U937 cells pretreated with
HL-60 cells when treated immediately 24 nM 1,25(OH)2D3 for 1 day before
after infection, suggesting a delay time infection. Opposed results were
between the stimuli addition and the communicated by Kitano et al., showing
susceptibility to viral infection. In a that a regime of 10-7 M 1,25(OH)2D3 for
model of chronically infected HL-60 cell 5 days prior to infection totally inhibited
line (HIV-1JR-FL), 1,25(OH)2D3 enhanced X4 replication and had no influence on
virus production more than 10-fold and the R5 strains HIV-1JR-FL and HIV-1BaL
induced the same phenotypic changes as (no infection at all) [150]. The role of
observed in uninfected cells. HL-60 cells 1,25(OH)2D3 in modulation of HIV-1
treated with 1,25(OH)2D3 (10 nM) production in chronically infected U937
showed increased CXCR4 mRNA cell line was in agreement with the data
expression after 3 days of stimulation reported in HL-60 cell line; 1,25(OH)2D3
[152,153] and 1 mM of 1,25(OH)2D3 at 1mM induced a elevated release of
increased the viral production of the infectious viral particles (14-fold) after 6
HTLVIIIB strain (X4) [150]. On the other days in culture. The authors observed no
hand in HL-60 cells a 30% inhibition of differences in the amounts of endogenous
CXCR4 surface expression has been TNF-Į production in control and
reported after 3 days of 1,25(OH)2D3 1,25(OH)2D3 treated cells, but there was
stimulation at 600 nM without any a clear upregulation of the TNF-Į
change in mRNA amount [154]. receptor [18].
However, although CXCR4 surface X4 chronically infected U937 cells,
expression was decreased upon treatment named U1 cells, produces HIV-1 particles
with 1,25(OH)2D3, it enhanced the only after induction with several stimuli
functional G-protein coupling to the such as INF-Ȗ, IL-6, GM-CSF or TNF-Į.
receptor as demonstrated by the increase The 1,25(OH)2D3 treatment alone (10-8
in SDF-1-mediated GTP binding [154]. M for 5 days) did not induce any increase
The U937 cell line was established from a in virus replication but co-treatment with
hystiocytic lymphoma [155]. This cell TNF-Į resulted in 3-fold increase in virus
line shows a phenotype of myelo- production above that induced by TNF-Į
monocytic lineage (CD13+, CD15+, and alone. In clear contrast, 1,25(OH)2D3
CD33+). Naïve U937 cells, as HL-60 blocked the viral replication induced by
cells, are CD4+/CXCR4+/CCR5- being INF-Ȗ, IL-6, GM-CSF [159]. Single cell
vulnerable to infection by X4 strains but clones derived from the U937 cell line
resistant to R5 strains [156]. U937 cells isolated by limiting dilution exhibit
exposed to 10-6 M 1,25(OH)2D3 for 1 or differential susceptibility to HIV-1
2 days prior to infection with HIV-1BRU infection. The so called plus clones
(X4) displayed 5-fold increase in virus (UC12, UC14) supported viral replication
204

(X4 strains) more efficiently than original [165] reported that primary monocyte
U937 cell line; in contrast the minus derived MAC treated for 5 days with
clone (UC11) showed only very limited 1,25(OH)2D3 (10-8 M) were markedly
viral replication [160,161]. Remarkably, protected from HIV replication. Finally,
stimulation with 1,25(OH)2D3 Pauza et al. [157] observed large
upregulated HIV-1 X4 replication in variability and contradictory results in
minus clones to levels comparable to 1,25(OH)2D3 effects between MAC from
those observed in plus clones, however different blood donors, in some cases the
the plus clones did not show any changes treatment produced a 50% reduction in
in response to the treatment. The origin of viral replication but in others it induced a
this phenotype is controversial; appears to slight increase in viral production.
be related at least to the density of Another experimental strategy to evaluate
CXCR4 in cell membrane, lower in the effects of 1,25(OH)2D3 signaling on
minus clones; although there were no HIV-1 replication parameters has been
clear differences in mRNA levels, and done by evaluation of HIV-1 LTR
functional Ca++ mobilization in response promoter activity after 1,25(OH)2D3
to CXCL12 between both cell types stimulation in transfected HeLa, Cos-1
[162]. 1,25(OH)2D3 selectively induces a and U937 cells. 1,25(OH)2D3 stimulated
slight increase in CXCR4 expression on the LTR transcription in a dose-response
the cell surface in minus clones [163]. manner, with 4-fold induction with 100
The A3.5 cell line was established from nM 1,25(OH)2D3 [17]. We have observed
human bone cell cultures. This cell line the same effect in primary monocyte
shows a monocyte phenotype (HLA- derived MAC from healthy blood donors
DR+/CD15+/CD3-), and is susceptible to and more interestingly, the intensity of
infection by X4 and R5 HIV-1 strains the induction show a relationship with
[158]. A3.5 cells exposed up to 240 nM VDR BsmI genotype polymorphism
1,25(OH)2D3 for 1 day prior to infection (unpublished data from AC laboratory).
with HIV-1IIIB (X4) exhibited enhanced Data regarding the significance of
virus replication in a dose-dependent 1,25(OH)2D3 in the course of HIV-1
manner; augmentation was up to 104 fold infection are scarce; Arpadi et al. [10]
in the presence of 240 nM 1,25(OH)2D3 evaluated the effect of 1,25(OH)2D3
after 14 days of culture. supplementation in children and
THP-1 exposed to 10-7 M 1,25(OH)2D3 adolescents at a dosage of 105 IU every 2
for 5 days prior to infection with both R5 months and they found no difference in
strains HIV-1JR-FL and HIV-1BaL and the progression of HIV-1 disease as measured
X4 strain HIV-1IIIB, exhibited a boosted by CD4+ cell count, viral load, rate of
viral replication after 7 days of culture. disease progression or antiviral treatment
The effect of 1,25(OH)2D3 treatment on failure.
HIV-1 infection of primary monocyte- In conclusion, the 1,25(OH)2D3 effects
MAC has been evaluated in three on viral replication depend on several
different studied. parameters, specially the maturation stage
Skolnik et al. [158] observed up to 12- of the cells, the timing of treatment and
fold enhancement of HIV-1 replication probably individual genotypes for VDR
(R5) in viral cultures treated with and the genes coding for 1,25(OH)2D3
1,25(OH)2D3 (10-8 M) after 14 days post- metabolism enzymes. Additional efforts
infection. In contrast, Schuitemaker et al. will be necessary to unveil the specific
role of 1,25(OH)2D3 signaling in HIV-1
205

replication and receptors expression 8p23.1 locus that exhibits copy number
especially in primary cells from variation from 2 to 12 copies per diploid
monocyte/MAC lineage. The genome. ȕ-defensins are widely
upregulation of CXCR4 by 1,25(OH)2D3 expressed throughout human epithelia.
in cells of myeloid lineage have been More than 30 loci exist, but only 4
demonstrated by several studies [163], in (HBD1 to HBD4) have been studied in
this context the evaluation of the detail. Į-defensins 1-4 and ȕ-defensins 2-
influence of VDR genotypes on the in 3 show anti-HIV-1 activity in vitro and
vivo selection of X4 or double tropic the in vivo expression correlates with
R5X4 strains is warranted. MAC are protection in mother-to-child
capable to perform both hydroxylation transmission. Also strong associations
steps of the 1,25(OH)2D3 metabolism between high Į-defensin concentrations
suggesting a possible role of local and a decreased risk of partum and
1,25(OH)2D3 synthesis by myeloid cells, postnatal HIV transmission have been
so we cannot exclude the possibility that observed. On the contrary Į-defensins 5
1,25(OH)2D3 is already present in these and 6 increase HIV-1 infectivity and
cells, especially after initiation of might have a role in enhancing HIV-1
differentiation process, pathogen transmission through genital mucosa
encounter or cytokines stimulation. A [166]. The relationships between vitamin
promising experimental strategy could be D and defensin expression have not been
to test the effects of antagonists of studied in detail. One report described the
1,25(OH)2D3 or siRNA against VDR upregulation of defensins expression in
during the course of HIV-1 infection of mouse skin after UV stimulation
primary MAC as well as the use of mediated by vitamin D production [167];
steroids deprived serum (charcoal-dextran in humans, the defensin-ȕ2 promoter
treated) or ketoconazole (24 hydroxylase contains a VDRE and the gene
inhibitor). transcription can be slightly enhanced at
24 hours by 1,25(OH)2D3 (1,5-2,0 fold)
Vitamin D action on innate immune in epithelial cells but not in neutrophils or
response has contrasting effects on HIV monocytes. On the contrary,
infection. The most well characterised 1,25(OH)2D3 partially blocks the
antimicrobial peptides in humans are defensin-ȕ2 expression at 48 hours in
defensins and cathelicidin (also named head and neck squamous carcinoma cells
LL-37). and adult keratinocytes [49].
Defensins are a family of microbicide and In humans there is only one cathelicidin
cytotoxic peptides involved in innate gene and is expressed on all epithelial
defense. They are abundant in the surfaces (mouth, tongue, esophagus,
granules of neutrophils (5% of total lungs, intestine, cervix and vagina, sweat
protein content) and also found in the glands, etc.) and by circulating white
epithelia of mucosal surfaces such as cells, including neutrophils, monocytes,
those of the intestine, respiratory tract, natural killer cells, and Ȗ˜T cells. In
urinary tract, skin and vagina. Members general, the expression of cathelicidin in
of the defensin family are highly similar most epithelial sites is constitutive but
in protein sequence and distinguished by can be increased by local injury or
a conserved cysteine motif. infection. The interaction between
Į-defensins and most of the ȕ-defensins vitamin D signaling and cathelicidin
genes are clustered on chromosome expression has been described in detail;
206

cathelicidin gene is a direct target of B mRNA-editing enzyme-catalytic


VDR, its promoter contains a VDRE and polipeptide-like-3G (APOBECG3) has
vitamin D treatment induces a strong up- raised special interest as interfering agent
regulation of cathelicidin mRNA. of HIV dissemination. APOBECG3
Cathelicidin is able to block HIV-1 belongs to a family of cytidine
infection in vitro [168, 169] but the deaminases that, in absence of the viral
concentration needed to reach 50% protein Vif, is incorporated in the nascent
inhibition of infection (30-50 mg/ml) is viral particle. Virions carrying
more than 2000 fold higher that the mean APOBECG3 express cytidine deaminase
concentration observed in samples from activity during reverse transcription that
cervicovaginal secretions (13 ng/ml, induces deamination of cytosines to
range 2-191 ng/ml) [170]. The same uracil, resulting in G to A hypermutation
study observed that the presence of on DNA sense strand. Hypermutated viral
sexually transmitted infections was DNA leads to aberrant viral products
associated with higher risk of HIV-1 aborting viral propagation [173].
acquisition (especially N. gonorrhoeae, Antiviral APOBECG3 activity can be
C. trachomatis or both) and increased abrogated by the interaction with viral
levels of several defensins and protein Vif that induces proteasoma-
cathelicidin. dependent degradation of APOBECG3.
Cathelicidin is an agonist of the formyl Studies on exposed uninfected individuals
peptide receptors and induces increased (EUI) indicate that variations on
cell migration, phagocytosis and release APOBECG3 levels might influence
of proinflammatory mediators [171], vulnerability to HIV infection.
being the neutrophils, monocytes, and T APOBECG3 expression is up-regulated
cells the main target cells; this peptide has by interferon family polypeptides, mainly
also been related to neovascularization IFN-Į, but also IFN-Ȗ, induced in
and wound healing [172]. We response to viral exposure [174].
hypothesize that although cathelicidin Expression levels of IFN-Ȗ vary among
shows minor antiviral effect at T-helper subtypes, being mainly
physiological concentration [168-170], it expressed after Th1-polarization.
might induce a more permissive Following this, it has been shown that
environment for HIV-1 replication CD4+ T-helper type 2 lymphocytes
through attraction of neutrophils, express lower levels of APOBECG3 than
monocytes and T cells to the tissues T-helper type 1 lymphocytes. As a result,
exposed to viral infection [170]. New data differences on infectivity among Th1 and
concerning the functional relationship Th2-produced HIV particles have been
between antimicrobial peptides levels, correlated with changes in APOBECG3
HIV-1 susceptibility and polymorphisms expression levels [175]. It is tempting to
in VDR or the enzymes of vitamin D speculate that the 1,25(OH)2D3-mediated
synthesis and degradation might give us a inhibition of IFN-Ȗ production [63] that
more accurate model of the complex contributes to inhibition of Th1
interaction between this arm of innate polarization and the subsequent
immune response and HIV-1 infection. In displacement to a Th2 profile could be
addition to microbicide and cytotoxic reflected as a lower expression of
peptides, host factors with specific APOBECG3 that favors not restricted
antiviral properties have been described. Th2-produced HIV particles. Evaluation
Among them, the human apolipoprotein of APOBECG3 response on CD4+ T cells
207

to 1,25(OH)2D3 treatment could be of 12 and IFN-Ȗ as a result of the interaction


interest to assess this hypothesis. of HIV-1-specific T cells with APC
inducing CTL dysfunction [178-180]. IL-
Vitamin D action on acquired immune 12 is a key cytokine required for the
response: tolerogenic vs. activation correct priming of CD4+ T cells to
strategies on HIV infection persistence provide help to CD8+ T cells to respond
Although immunopathogenesis of HIV to HIV infection [181]. In addition, as for
infection has been largely studied, vitamin D mediated induction of IL-10,
mechanisms underlying viral persistence HIV Tat protein, a key virus protein
and inability of host immune response to involved in viral replication, interferes on
control infection remain obscure. T cell host cytokine production by the induction
immune responses, that are capital for the of IL-10 [182]. IL-10 cytokine is up
control of many viral infections, are often regulated during HIV infection
unable to control HIV replication. The contributing to maintain a tolerogenic
incapability to mount an efficient T cell status that favours HIV mediated
response seems to be a common feature immunodeficiency. Finally, it has been
of chronic viral infections that, in addition proposed by several authors that the Th2-
to HIV, also include hepatitis virus B polarization that characterises HIV
(HVB) and C (HVC) infections. It has infection could resemble an allergic
been found that viruses causing persistent response to viral antigens [183,184] and
viral infection develop a variety of that gp120 envelope and Tat viral
strategies to evade or overcome the host proteins could act as potent viral allergens
immune response. Among mechanism [185-188]. Also, a high frequency of
developed on such a way, avoiding T cell hypersensitivity reactions in HIV infected
activation by the promotion of a patient has been described contributing to
tolerogenic status [176] and induction of HIV disease progression [184]. As
T cell exhaustion by T cell formerly mentioned, vitamin D promotes
overstimulation [177], are two strategies allergy [115] and predisposes to allergic
used by HIV to evade an efficient T cell syndromes [116]. Following this, vitamin
mediated immune response. We can D could contribute to reinforce the HIV-
expect contrasting effects of vitamin D promoted allergy associated with disease
immunomodulation on these two progression.
mechanisms. Despite the presence of HIV induced
HIV infection is characterised by several immunodeficiency, almost all cellular
disturbances in the cytokine expression components of the immune system, B
pattern. Among these, a general decrease cells, NK cells, T cells and MAC show
in the expression of pro-inflammatory evidence of immune activation. Early
cytokines, as a consequence of a reduced steps of HIV infection are characterised
Th1 polarization, seems to contribute to by an acute T cell response, mainly CD8+
the host-inability for mounting a proper T T cells, which can be maintained during
cell mediated response [107]. It is the chronic phase of infection, and with a
remarkable that vitamin D and HIV lower magnitude CD4+ T cells, probably
infection exert similar action on Th1- due by their preferential depletion by the
Th2-polarization, both favouring Th2 virus [189]. In addition, microbial
polarization. As for vitamin D action on products, mainly derived from the
Th cell polarization, HIV infection is gastrointestinal tract, contribute to HIV-
characterised by a down-regulation of IL- related systemic immune activation [190].
208

In spite of this T cell response, HIV concerns have been raised about this
infection can be established and reach strategy; changing initial parameters may
successful persistence. Paradoxically, T have effects on long-term infection, by
cell activation, that may be considered a establishing a new immunological set
positive response against viral pathogens, point that may affect the rate of disease
could be detrimental in the context of progression [198].
HIV infection, as, new targets for viral It is intuitive to consider vitamin D
replication, in particular CD4+ T cells, treatment as an immunomodulatory
can contribute to promote HIV infection. adjuvant in HIV infection. As previously
This intuitive observation is supported by mentioned, vitamin D acts on T cell
experimental data indicating that there is polarization promoting Treg cells while
indeed a direct correlation between T cell inhibiting T effectors cells, mainly Th1
activation levels and HIV disease cells. Thus, vitamin D may contribute to
progression [191,192]. This paradoxicall avoid the early exacerbating T cell
effect of immune activation is exploited response, that HIV could have taken in
and promoted by HIV in a perverse advantage. Nevertheless, the contribution
strategy [193,194]. of Treg on HIV infection must to be
Under continuous HIV-induced T cell considered with caution as beneficial and
activation an altered homeostasis of T detrimental effects can be expected [199].
cells (i.e., T cell turnover and apoptosis) In support for a beneficial effect of Treg
is observed. Continuous and persistent on HIV infection is the negative
differentiation of naïve T lymphocytes to association between Tregs and immune
antigen experienced cells and subsequent activation showed during HIV infection
apoptosis reach boundaries on the [200] that may contribute to the
regenerative capacity of the immune attenuation of HIV-specific T cell
system. As a consequence HIV infected immune responses in the early stages of
individuals loose their capability to HIV disease [201]. On the other hand, in
replenish naïve T cell pool exhibiting support for a detrimental effect is i) the
characteristics of replicative senescence association of Treg cells with more severe
[195] that exhaust the capacity of the stages of infection and ii) induction of
immune system to control HIV infection Th2 polarization [202]. The increase in
[177]. Treg function could impair cellular
It has been proposed by several authors immunity able to block HIV spread. In
that suppression of the activated immune the simian immunodeficiency virus (SIV)
response in HIV infection can contribute infection model a premature induction of
to control infection. In fact, antiretroviral immunosuppressive regulatory cells has
therapy (ART), which is until now the been shown contributing to viral
best strategy to combat infection, inhibits persistence by limiting early antiviral
HIV replication by contributing to the response [176].
deactivation of the immune responses in Another concern about using vitamin D
HIV infected individuals [196]. as immunosuppressant agent on HIV
Treatment of HIV infection with infection comes from the expected
immunosuppressant drugs as ART promotion of T cell exhaustion and viral
coadjuvants has been considered, persistence induced by vitamin D derived
assuming that a decreased immune cytokine pattern. As pointed before,
activation associated with HIV infection vitamin D induces Th2 cells, with an IL-
may be beneficial [197]. However 4, IL-5 and IL-10 cytokine profile, and
209

Treg cells, with a TGF-ȕ and IL-10 single haplotype block of the promoter
cytokine profile. IL-10 is an VDR region [208].
immunomodulatory cytokine that In addition, a common FokI
attenuates inflammatory response by polymorphism (rs10735810) has been
suppressing Th1 cytokine production and described in the VDR coding region that
proliferation of CD4+ and CD8+ cells alter the first ATG start site to an
[203]. Recently, a key role of IL-10 alternate ACG sequence. By this
cytokine on T cell exhaustion and viral polymorphism two potential starting sites
persistence has been proposed [204]. for the VDR translation appear [209].
Increased IL-10 production has been Messenger RNA transcripts with the
reported during persistent viral infection ACG sequence begin translation three
of lymphocytic choriomeningitis virus codons downstream, giving raise to a
(LCMV), whereas anti-IL10 receptor VDR protein that is three amino acids
antibodies unleash the viral persistence shorter (424 aa vs 427 aa). Functional
[205]. Thereafter, IL-10 receptor differences among FokI genotypes show
antagonists have been proposed for the that VDR protein coded by the F-VDR
treatment of chronic viral infections in (short, 424 aa) allele interacted more
humans [206]. Thus, vitamin D-induced efficiently with Transcription Factor II B
IL-10 production could contribute to (TFIIB) and showed greater
virus persistency and favouring viral transcriptional activity than the full-
persistence. length VDR protein coded by f-VDR
allele [210]. The impact of FokI
Lessons from Vitamin D receptor polymorphism on 1,25(OH)2D3-VDR
polymorphisms and association studies. mediated immune modulations has been
Several VDR polymorphisms have been recently evaluated [211]. The shorter F-
described in the regulatory, coding and 3’ VDR form was linked to a higher
UTR region with functional effects transcriptional activity driven by NF-țȕ
(Figure 8). Two common polymorphisms, and NFAT motif as well as IL-12p40
Cdx (rs1568820) and A1012G promoter-driven transcription.
(rs4516035), have been located in the 5’ Consequently it was shown that
regulatory region that influence binding monocytes and DCs of homozygous
of transcription factors. The Cdx subjects for short F/F VDR genotype
polymorphism is a G to A transition express higher IL-12 mRNA and protein
located between exons 1f and 1e that than cells with a long f/f VDR genotype,
alters the recognition site for the concluding that the short F-VDR allele is
intestinal-specific transcription factor associated with a more active immune
caudal-related homeodomain protein response.
(Cdx)-2 affecting 1,25(OH)2D3-VDR Finally, three restriction fragment length
mediated intestinal calcium absorption polymorphisms (RFLP), designed as
[207]. The A1012G polymorphism is an BsmI (rs1544410), ApaI (rs7975232) and
A to G transition located between 1e and TaqI (rs731236), and a PolyA
1a exons that modify the GATA binding (rs17878969) microsatellite
protein (GATA)-3 transcription factor polymorphism have been described in the
recognition sequence, involved in the 3’-UTR region of the VDR gene,
regulation of Th2 polarization. Cdx-2 and showing strong linkage disequilibrium in
GATA promoter SNPs are included in Caucasian population [212,213].
210

Functional effects of 3’-UTR variants RFLP, cut allele, and TaqI RFLP, uncut
have been related to alterations in VDR allele) was associated with decreased IL-
mRNA stability [208]. Functional effects 12p40 and IFN-Ȗ and increased IL-10
of 3’UTR haplotypes on VDR mediated cytokine response of 1,25(OH)2D3 treated
immune modulation have been evaluated. peripheral blood mononuclear cells [214].
Haplotype b-a-T (for BsmI and ApaI

Figure 8. The most relevant VDR polymorphic markers are positioned all along VDR
gene structure as in Figure 3. Two markers are located in the promoter-5’UTRs region,
rs11568820 (Cdx) upstream exon 1e and rs4516035 (A1012G) between exons 1e and 1a.
Marker rs2228570 (FokI) is located in exon 2. Finally, four additional markers are located
in the 3’UTR region, rs1544410 (BsmI) and rs7975232 (ApaI), between exons 8 and 9 and
rs731236 (TaqI) and rs17878969 (PolyA) in exon 9. SNP markers rs11568820, rs4516035,
rs2228570, rs1544410, rs7975232 and rs731236 are biallelic. Marker rs17878969 is a
mononucleotide repeats of adenines, showing a bimodal distribution of allele frequency
[213] with short (S) allele expanding 18 A repeats and long (L) allele expanding 24 A
repeats. Alleles have been coded according to coding VDR sequence. For restriction
fragment length polymorphism (FokI, BsmI, ApaI and TaqI) alleles are also coded
according to cutting (small letter) and un-cutting (capital letter) alleles. Functional effects
of polymorphic variants on immune function are depicted at the bottom of the Figure.
211

This seems to indicate that 1,25(OH)2D3- suggested that the promoter Cdx-A1012G
VDR mediated Th1 polarization is (G-A) haplotype and the 3’ UTR
haplotype dependent with the b-a-T haplotypes containing the BsmI-b allele
haplotype producing the lower Th1 are associated with protection to HIV-1
polarization effect. infection. Since protective haplotypes
The 3’ UTR polymorphisms have been confers a lower efficiency on the vitamin
associated with increased susceptibility to D pathway, it was inferred that
infection by bacteria and viruses, hampering vitamin D signaling could
including Mycobacterium tuberculosis confer protection to HIV-1 transmission.
[215,216], Mycobacterium leprae [217],
Dengue Virus [218], Human T-cell 7. CONCLUDING REMARKS:
Lymphotropic Virus Type 1 (HTLV-1) VITAMIN D, FRIEND OR FOE IN
[219], HBV [220] and Respiratory HIV INFECTION? There is a general
Syncytial Virus [221]. agreement that vitamin D sufficiency
1,25(OH)2D3-mediated signals appear to contributes to good health, being essential
have a protective role in tuberculosis, in to regulate the absorption and metabolism
vitro [15] as well as in vivo [216, 222]. of calcium and phosphorus resulting in
However, in vivo 1,25(OH)2D3 treatment health bones [226]. In addition, vitamin D
exhibits a negative influence on the protects from bacterial infections and
clinical course of both toxoplasmosis helps against cell proliferation that could
[223,224] and leishmaniosis [16] in give rise to cancer cells. Public concern is
mouse. On the contrary, a clinical trial about vitamin D insufficiency that seems
evaluating the effect of vitamin D as to affect a great proportion of the
supplementary treatment for tuberculosis population in both developed and
showed no overall effect on human developing countries. However, we
beings [225]. would have to be cautious about vitamin
In the context of HIV-1 infection, two D contribution to a chronic and persistent
VDR polymorphisms (BsmI and FokI) infection such as HIV. We have found in
have been associated with susceptibility the literature evidences supporting a
to faster progression towards AIDS- protective role of vitamin D in HIV
defining illness on a Spanish cohort of infection by inducing antimicrobial
HIV-1 positive intravenous drug users. agents and modulating host to exacerbate
BsmI B/B homozygotes [22] and FokI F/f immune responses. Nevertheless, we have
heterozygotes [21] were over represented also found solid data bearing for a
among those reaching AIDS outcome. deleterious role of the hormone by
Both genotypes are associated with promoting HIV replication and helping
functional effects, enhanced VDR activity virus on HIV-escape strategies. The
(FokI-F allele) and increased mRNA major mistake we can do is to try to
stability (BsmI-B allele). Apart from the resolve this dilemma in terms of friend
association of VDR gene variants with and foe. There is no a single and simple
progression to AIDS, these gene variants answer that allows us to understand the
could also influence the susceptibility to complexity of this phenomenon.
HIV-1 infection. Studies comparing There is no data in the literature about the
Spanish HIV-1 positive intravenous drug effect of HIV-1 infection in the
users versus HIV-1 exposed uninfected expression of VDR and vitamin D-related
controls [20] and Indians HIV-1 positive enzymes. In the case of the chronic
versus healthy controls [19] had retroviral infection with MuLV, it has
212

been observed an alteration on both the been considered an alternative strategy


local vitamin D metabolism and the VDR for enhancing the effectiveness of
expression by immune cells [227]. Over different prophylactic and therapeutic
30% of the myeloid cells from MuLV HIV-vaccine strategies [229]. Vitamin D
infected mice expressed VDR, whereas inhibits APC maturation and antigen
less than 1% of the uninfected cells did presentation acting as antigen-
so. This suggests that the retroviral presentation attenuator. Subsequently, the
infection induces the VDR expression in use of VDR antagonist and/or inhibitors
monocyte/MAC. There is a correlation of the vitamin D pathway enzymes could
between the increase in functional be proposed as co-adjuvants in HIV
receptor protein and an increased therapeutic approaches. Further
response to 1,25-(OH)2D3 in many cell investigations are warranted to develop
systems [5]. In this retroviral infection the vitamin D-related drugs that, avoiding
vitamin D treatment leads to increased non-desired side effects, could be used in
cytopathic effects and lower survival. such strategies.
Unfortunately a similar experimental
approach has not been investigated in the 8. ACKNOWLEDGMENTS. Authors’
case HIV-1 infection. Although the work was supported by Grants “Fondo de
literature about vitamin D and HIV-1 is Investigaciones Sanitarias” (FIS) to J.F.
abundant, some critical questions remain (ref.: PI021476 and PI051778) and A.C.
to be solved. The relationship between (ref.: PI021205). “Fundació Marató TV3”
vitamin D metabolism and HIV-1 to J.F. (ref.: 020730) and A.C. (ref.:
infection might be elucidated using an 020732).
approach that might include: investigate
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