ReviewVitamin D supplementation and antibacterial immune responses in adolescents and young adults with HIV/AIDS☆
Introduction
Vitamin D promotes a range of extra-skeletal responses that may impact on diverse aspects of human physiology [1]. Prominent amongst these are the immunomodulatory effects of active 1,25-dihydroxyvitamin D (1,25(OH)2D), that can influence both innate and adaptive immunity [2], [3]. Responses to 1,25(OH)2D are mediated via the nuclear vitamin D receptor (VDR) which is expressed by many immune cells [4]. However, monocytes are particularly important targets for vitamin D because they express the enzyme 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) that catalyzes conversion of pro-hormone 25-hydroxyvitamin D (25OHD) to active 1,25(OH)2D [5], [6]. The resulting intracrine mechanism plays a pivotal role in innate antibacterial responses, where binding of pathogen-associated molecular patterns (PAMPs) to monocyte pattern-recognition receptors (PRR) stimulates expression of both VDR and CYP27B1 [7]. Intracrine conversion of 25OHD to 1,25(OH)2D by monocytes promotes several antibacterial responses, including enhanced expression of antibacterial proteins [7], [8], induction of autophagy [9], [10], and regulation of intracellular iron homeostasis [11]. These effects appear to be dependent on the availability of substrate 25OHD for intracrine conversion to 1,25(OH)2D. As 25OHD is the main circulating form of vitamin D, variations in serum 25OHD status have the potential to influence monocyte antibacterial responses, with vitamin D-deficiency compromising, and vitamin D-supplementation enhancing, antibacterial responses [7], [12].
Vitamin D-induced antimicrobial responses have been reported for several different cell types and may occur in response to a variety of pathogens [3]. In particular, vitamin D-induced antibacterial responses in monocytes have been closely linked to mycobacterial infections such as tuberculosis [13]. The tuberculosis pathogen Mycobacterium tuberculosis (M. tb) is phagocytosed by monocytes and macrophages, but M. tb PAMPs also promote innate immune responses when recognized by PRR such as the toll-like receptor (TLR) 2/1 heterodimer [14], [15]. TLR2/1 ligands (TLR2/1L) associated with M. tb have been shown to stimulate monocyte expression of CYP27B1 and VDR, with the resulting intracrine induction of the antibacterial protein cathelicidin (CAMP) acting to promote intracellular killing of M. tb [7].
These observations provide a mechanistic rationale for the historical link between vitamin D and the treatment of tuberculosis, in which ultraviolet light (the primary mode of vitamin D generation in normal physiology) and cod liver oil (a rich source of dietary vitamin D) were at one time used as a treatment for tuberculosis [16], [17]. More recently, epidemiology has shown that vitamin D-insufficiency is associated with increased incidence of tuberculosis [18], [19], [20], [21], and several clinical trials of vitamin supplementation and tuberculosis have also been reported with varying degrees of success [21], [22], [23], [24]. Vitamin D-deficiency is also prevalent in HIV+ subjects where there is increased risk of infection by pathogens such as M. tb [25], [26]. Supplemental vitamin D may help to promote antibacterial responses in HIV+ subjects by utilizing intracrine vitamin D pathways [27]. However, vitamin D may also stimulate anti-retroviral responses in the setting of HIV-infection, with a recent study showing that 1,25(OH)2D-induced autophagy in macrophages not only stimulates killing of M. tb, but also inhibits replication of HIV [28]. To investigate the possible importance of vitamin D for antibacterial responses in HIV+ subjects, we carried out two vitamin D supplementation trials and used serum from the trial participants to assess monocyte antibacterial activity. Furthermore, we investigated potential differences in anti-bacterial responses in HIV+ subjects compared to healthy control subjects (HIV−) of similar age and serum vitamin D status.
Section snippets
Human subjects
Subjects with HIV were recruited from Philadelphia regional urban centers for two vitamin D supplementation trials. Both protocols were approved by Institutional Review Board at CHOP. Written informed consent was obtained from subjects ages 18.0 to 24.9 years, emancipated minors presenting for care alone and parents/legal guardians of subjects <18.0 years. Healthy control subjects were drawn from two studies, one investigating vitamin D status in subjects with sickle cell disease and one in
Characteristics of HIV+ and HIV− patient cohorts
HIV+ subjects in the Dose Study (n = 40) and the RCT (n = 56) and healthy control subjects (n = 20) were similar in age, sex and racial background to subjects with HIV+, however, a greater proportion of HIV+ subjects had 25OHD deficiency (Supplemental Table 1). Approximately half of HIV+ subjects had detectable RNA viral load and 75% were receiving highly active anti-retroviral therapy (HAART) at the time of the study.
Induction of 25OHD and 1,25(OH)2D metabolism (CYP27B1 and CYP24A1) and VDR expression in monocytes cultured with HIV+ and HIV− serum
Serum from HIV+ subjects at baseline and from age-matched HIV− control subjects was
Discussion
Vitamin D-deficiency is common to populations across the globe [36], but appears to be particularly prevalent in subjects with HIV [37], [38], [39]. The underlying cause of this has yet to be fully defined and likely includes general factors commonly associated with vitamin D-deficiency such as seasonal and skin pigmentation variations that affect epidermal synthesis of vitamin D by UV light. However, additional HIV-specific factors may further compromise vitamin D status in HIV+ subjects,
Acknowledgements
We are grateful to subjects and families for participation. We thank Julia Samuel, Savannah Knell, Susan Ellenberg, PhD, Steven Douglas, MD, Kelly Dougherty, PhD, Florin Tuluc, PhD, Eric Riedel, Jennifer Murray, Clinical Translational Research Center, the Special Immunology Family Care Clinic, Adolescent Initiative Program at CHOP, Jonathan Lax Treatment Center, Cooper University Hospital, Alfred I DuPont Hospital for Children, Hospital of the University of Pennsylvania, Temple University
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This work was supported by the NIH/National Center for Complementary and Alternative Medicine, Grant R01AT005531, the National Center for Research Resources, Grant UL1RR024134, and is now at the National Center for Advancing Translational Sciences, Grant UL1TR000003. Ex vivo analyses were supported by NIH/NIAMS grant AR063910.