Abstract
Human monocytes activated by toll-like receptor 2/1 ligand (TLR2/1L) show enhanced expression of the vitamin D receptor (VDR) and the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1). The resulting intracrine conversion of precursor 25-hydroxyvitamin D3 (25OHD) to active 1,25-dihydroxyvitamin D (1,25(OH)2D) can stimulate expression of antibacterial cathelicidin (CAMP). To determine whether this response is functional in HIV-infected subjects (HIV+ ), serum from HIV+ subjects pre- and post-vitamin D supplementation was utilized in monocyte cultures with or without TLR2/1L. Expression of CYP27B1 and VDR was enhanced following treatment with TLR2/1L, although this effect was lower in HIV+ vs HIV- serum (p<0.05). CAMP was also lower in TLR2/1L-treated monocytes cultured in HIV+ serum (p<0.01). In a dose study, supplementation of HIV+ subjects with 4000IU or 7000IU vitamin D/day increased serum 25OHD from 17.3±8.0 and 20.6±6.2ng/ml (43nM and 51nM) at baseline to 41.1±12.0 and 51.9±23.1ng/ml (103nM and 130nM) after 12 weeks (both p<0.001). Greater percent change from baseline 25OHD was significantly associated with enhanced TLR2/1L-induced monocyte CAMP adjusted for baseline expression (p=0.009). In a randomized placebo-controlled trial, 7000IU vitamin D/day increased serum 25OHD from 18.0±8.6 to 32.7±13.8ng/ml (45nM and 82nM) after 12 weeks. Expression of CAMP increased significantly from baseline after 52 weeks of vitamin D-supplementation. At this time point, TLR2/1L-induced CAMP was positively associated with percent change from baseline in 25OHD (p=0.029 overall and 0.002 within vitamin D-supplemented only). These data indicate that vitamin D supplementation in HIV-infected subjects can promote improved antibacterial immunity, but also suggest that longer periods of supplementation are required to achieve this.