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J Biol Chem. 2011 May 27;286(21):18890-902. doi: 10.1074/jbc.M110.206110. Epub 2011 Mar 30.

Hormonally active vitamin D3 (1alpha,25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection.

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  • 1Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California 92093, USA.

Abstract

Autophagy is a self-digestion pathway essential for maintaining cellular homeostasis and cell survival and for degrading intracellular pathogens. Human immunodeficiency virus-1 (HIV-1) may utilize autophagy for replication as the autophagy-related protein-7 (ATG-7), microtubule-associated protein 1 light chain 3, ATG-12, and ATG-16L2 are required for productive HIV-1 infection; however, the effects of autophagy induction on HIV-1 infection are unknown. HIV-1-infected individuals have lower levels of 1α,25-dihydroxycholecalciferol, the hormonally active form of vitamin D, than uninfected individuals. with the lowest concentrations found in persons with AIDS. Using human macrophages and RNA interference for ATG-5 and Beclin-1 and chemical inhibition of phosphatidylinositol 3-kinase, we have found that physiologically relevant concentrations of 1α,25-dihydroxycholecalciferol induce autophagy in human macrophages through a phosphatidylinositol 3-kinase-, ATG-5-, and Beclin-1-dependent mechanism that significantly inhibits HIV-1 replication in a dose-dependent manner. We also show that the inhibition of basal autophagy inhibits HIV-1 replication. Furthermore, although 1α,25-dihydroxycholecalciferol induces the secretion of human cathelicidin, at the concentrations produced in vitro, cathelicidin does not trigger autophagy. Our findings support an important role for autophagy during HIV-1 infection and provide new insights into novel approaches to prevent and treat HIV-1 infection and related opportunistic infections.

PMID:
21454634
[PubMed - indexed for MEDLINE]
PMCID:
PMC3099705
Free PMC Article
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