Vitamin D-related host genetic variants alter HIV disease progression in children.

Vitamin D is traditionally associated with calcium homeostasis and bone mineralization, but recent work has shed light on its role as an important regulator of both innate and adaptive immunity (1-3). The immune modulating effects of vitamin D are mediated by the binding of biologically active 1,25 dihydroxy (OH) vitamin D to vitamin D receptors (VDRs) within macrophages, dendritic cells, neutrophils, B cells, and activated T lymphocytes (4,5). Vitamin D regulates the release of specific cytokines, modifies T lymphocyte proliferation and function, and increases the production of antimicrobial peptides like cathelicidin (3,6-8). Furthermore, vitamin D has been shown to increase autophagy, a cellular process utilized by immune cells to kill intracellular pathogens through increased phago-lysosomal fusion (9,10). In vitro studies have demonstrated that autophagy induced by physiological concentrations of 1,25(OH) vitamin D, leads to inhibition of human immunodeficiency virus type-1 (HIV) replication in HIV-infected macrophages (11). Low levels of vitamin D have been associated with increased susceptibility to several infectious diseases including HIV, and have been associated with worse outcomes in these patients (12-14). Children, adolescents and adults who are infected with HIV have been reported to have a high prevalence of vitamin D deficiency (15-23). In large studies of European and North American HIV-infected adults, low levels of vitamin D (defined as 25 hydroxy vitamin D levels <30 ng/ml) were found in 89% and 70.3% of patients, respectively (15,16). Children infected with HIV were found to have a similarly high prevalence of vitamin D insufficiency and deficiency (17,20). Low levels of both 25(OH) vitamin D and biologically active 1,25(OH) vitamin D have been associated with advanced clinical stage of HIV infection, lower CD4 counts and increased mortality (16,23,24). In HIV infected pregnant women not receiving HAART, vitamin D deficiency was associated with progression to World Health Organization HIV stage III or greater, severe anemia and all cause mortality (13). Infants born to these mothers had a significantly higher risk of acquiring HIV infection during the perinatal and postnatal period, and were more likely to die during follow-up regardless of HIV infection status (25). Furthermore, these infants had an increased risk of stunting and being underweight (26). Factors associated with low vitamin D levels in HIV infection include obesity, black or Hispanic race, exposure to HIV drugs like efavirenz, renal insufficiency, darker skin pigmentation, higher latitude, inadequate vitamin D dietary intake and lower exposure to ultraviolet light (15,19,20,23,27). Host genetic variants associated with low serum 25(OH) vitamin D levels have been described in large genome-wide association studies but not in HIV-infected persons (28-30). Genetic variants that lead to altered activity of vitamin D, however, have been reported in adult HIV-infected intravenous drug users and include single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene (31-34). Taken together these findings suggest that factors that alter the availability or function of biologically active vitamin D are important in determining susceptibility to HIV infection and in predicting the rate of progression to advanced disease. The present study investigated the role of five vitamin D related host genetic variants (GC [group-specific component (vitamin D binding) protein], Fok-I, Bsm-I, DHCR7 and CYP2R1) in HIV disease progression in a cohort of HIV-infected children who participated in the Pediatric AIDS Clinical Trials Group (PACTG) P152 and P300 protocols that pre-dated the availability of effective combination antiretroviral therapy (35,36).