Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1

PLoS Pathog. 2012;8(11):e1003017. doi: 10.1371/journal.ppat.1003017. Epub 2012 Nov 15.

Abstract

Toll-like receptors (TLR) are important in recognizing microbial pathogens and triggering host innate immune responses, including autophagy, and in the mediation of immune activation during human immunodeficiency virus type-1 (HIV) infection. We report here that TLR8 activation in human macrophages induces the expression of the human cathelicidin microbial peptide (CAMP), the vitamin D receptor (VDR) and cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1), which 1α-hydroxylates the inactive form of vitamin D, 25-hydroxycholecalciferol, into its biologically active metabolite. Moreover, we demonstrate using RNA interference, chemical inhibitors and vitamin D deficient media that TLR8 agonists inhibit HIV through a vitamin D and CAMP dependent autophagic mechanism. These data support an important role for vitamin D in the control of HIV infection, and provide a biological explanation for the benefits of vitamin D. These findings also provide new insights into potential novel targets to prevent and treat HIV infection.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 25-Hydroxyvitamin D 2 / immunology
  • 25-Hydroxyvitamin D 2 / pharmacology*
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase / immunology
  • Antimicrobial Cationic Peptides / immunology
  • Autophagy / drug effects*
  • Autophagy / immunology
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / immunology
  • HIV-1 / metabolism*
  • Humans
  • Ligands
  • Male
  • Receptors, Calcitriol / immunology*
  • Toll-Like Receptor 8 / agonists*
  • Vitamins / immunology
  • Vitamins / pharmacology*

Substances

  • Antimicrobial Cationic Peptides
  • Ligands
  • Receptors, Calcitriol
  • TLR8 protein, human
  • Toll-Like Receptor 8
  • Vitamins
  • CAP18 lipopolysaccharide-binding protein
  • 25-Hydroxyvitamin D 2
  • 25-Hydroxyvitamin D3 1-alpha-Hydroxylase