Antiviral therapeutic approaches for human rhinovirus infections

Casanova, Victor; Sousa, Filipa H; Stevens, Craig; Barlow, Peter G

Humans primarily obtain vitamin D from solar exposure and from the diet. Solar ultraviolet B radiation converts 7-dehydrocholesterol to previtamin D3, which is rapidly converted to vitamin D3. Vitamin D3 from the skin or the diet is further converted to 25-hydroxyvitamin-D which circulates in serum and is used to determine the vitamin D status. Lung epithelial cells and immune cells can convert the circulating, inactive, 25-hydroxyvitamin-D to its active form, 1,25(OH) 2 D or calcitriol, which can engage the nuclear vitamin D receptor (VDR) and mediate its myriad of actions [92, 93, 94] , revealing an important health problem and the underscoring the possibility of intervention by vitamin D supplementation. The immediate consequence of nuclear VDR ligation is the heterodimerization with retinoid X receptor and the binding to vitamin D responsive elements in promoter regions of responsive genes. These genes include CAMP and DEFB4, which correspond to human cationic antimicrobial peptide of 18 KDa (hCAP-18/LL-37) and β-Defensin-2 (HBD2) of which both are HDPs [95] . Induction of LL-37 by vitamin D has been reported in several cell types, including lung epithelial cells, and of relevance, calcitriol (1,25-(OH) 2 D 3 ) delivery to human primary bronchial epithelial cells (HPBEC) 24 h prior to RV-16 infection proved sufficient to reduce viral replication by 2.8-fold in comparison to untreated cells [86] . This effect was also observed in cells from cystic fibrosis patients with a twofold reduction in virus. Importantly, CAMP but not DEFB4 mRNA expression was increased by vitamin D, and exogenous delivery of 20 μg/ml of recombinant LL-37 recapitulated the antiviral effects observed with vitamin D delivery. A subsequent study validated the antiviral effect of calcitriol pretreatment on the RV1B serotype, reducing both viral RNA and virion release from HPBEC [87] . These two studies show that calcitriol induces LL-37 and that > 20 μg/ml of exogenous LL-37 have a direct antiviral effect on RV, an activity that is conserved to other mammal cathelicidins [82] . future science group www.futuremedicine.com