Vitamin D receptor and epigenetics in HIV infection and drug abuse

Abstract

Illicit drug abuse is highly prevalent and serves as a powerful co-factor for HIV exacerbation. Epigenetic alterations in drug abuse and HIV infection determine expression of several critical genes such as vitamin D receptor (VDR), which participates in proliferation, differentiation, cell death under both physiological and pathological conditions. On that account, active vitamin D, the ligand of VDR, is used as an adjuvant therapy to control infection, slow down progression of chronic kidney diseases, and cancer chemotherapy. Interestingly, vitamin D may not be able to augment VDR expression optimally in several instances where epigenetic contributes to down regulation of VDR; however, reversal of epigenetic corruption either by demethylating agents (DACs) or histone deacetylase (HDAC) inhibitors would be able to maximize expression of VDR in these instances.

Keywords: HIV; alcoholism; cocaine; epigenetics; gene expression regulation; opioids; vitaimin D; vitamin D receptor.

FIGURE 1

VDR gene structure and regulation VDR target genes. (A) The genomic structure of the VDR gene on chromosome 12q13. The VDR gene spanning the 14 exons of the VDR gene. (B) Vit D binds VDR in the cytosol facilitating its translocation into the nucleus, followed by heterodimerization with RXR. VDR-RXR complex binds to vitamin D response elements (VDREs) on target genes leading to formation of either coactivator (with liganded VDR) or repressor (with unliganded VDR) complexes.

FIGURE 2

HIV-1 and drugs of abuse induced epigenetic Changes. Cells exposed to HIV-1 and drugs of abuse lead to similar epigenetic modifications. Drug and HIV milieus promote pro-inflammatory environment and induce epigenetic changes at the histone/DNA levels. Alcohol induces histone H3 and H4 acetylation. In contrast, morphine can lead to HDAC1 and HDAC2 recruitment to the histones preventing gene transcription. Morphine can cause epigenetic changes at the DNA level potentially resulting in increases in DMNT (DNA methyltransferase) recruitment to the DNA, leading to CpG methylation, which would prevent specific gene expression. *HDACs (histone deacetylases); **H3 and H4 (histone fractions); ***Me (methyl group).