1
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India.
2
Department of Chemical Engineering, Indian Institute of Technology Delhi, New Delhi, India.
3
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary sciences, New Delhi, India.
4
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi, India. Electronic address: [email protected].
PMID: 34562448 DOI: 10.1016/j.jbc.2021.101233
Free article
Abstract
Clinical and epidemiological studies support a role for vitamin D in suppressing hepatitis B virus (HBV). This antiviral role of vitamin D is widely attributed to Vitamin D Receptor (VDR)/Retinoid X Receptor (RXR)-mediated regulation of host immunomodulatory genes through Vitamin D Response Elements (VDREs) in their promoters. Here, we investigated the ability of calcitriol (1α,25(OH)2D3, metabolically activated Vitamin D) to directly regulate HBV activity through this signaling pathway. We observed that calcitriol selectively inhibited only the HBV-core promoter without affecting the HBV-PreS1, HBV-PreS2/S, or HBx promoters. We then identified a VDRE-cluster in the HBV-core promoter that is highly conserved across most HBV genotypes. Disruption of this VDRE-cluster abrogated calcitriol-mediated suppression of the HBV-core promoter. Furthermore, we showed VDR interacts directly with the VDRE-cluster in the HBV-core promoter independent of RXR. This demonstrates that calcitriol inhibits HBV-core promoter activity through a non-canonical calcitriol-activated VDR-pathway. Finally, we observed that calcitriol suppressed expression of the canonical HBV-core promoter transcripts, pregenomic RNA and precore RNA in multiple HBV cell culture models. Additionally, calcitriol inhibited the secretion of HBeAg and HBsAg (HBV-encoded proteins linked to poor disease prognosis), without affecting virion secretion. Our findings (a) identify VDR as a novel regulator of HBV-core promoter activity, (b) explain at least in part the correlation of vitamin D levels to HBV activity in clinical studies, (c) have implications on the potential use of vitamin D along with anti-HBV therapies, and (d) lay the groundwork for studies on vitamin D-mediated regulation of viruses through VDREs in virus promoters.
Keywords: Antiviral agent; Cell signaling; Gene regulation; HBV Core promoter; Hep B); Hepatitis B virus (HBV; Nuclear Receptor; Viral transcription; Vitamin D; Vitamin D Receptor (VDR); Vitamin D Response Element (VDRE).