title: Hormonally active vitamin D3 (1alpha,25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection.
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.
authors: Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California 92093, USA.
authors: Grant R
authors: GR
authors: Campbell
authors: Stephen A
authors: SA
authors: Spector
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000378:metabolism; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D002762:Cholecalciferol; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology; D014815:Vitamins / Q000494:pharmacology*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; D051017:Apoptosis Regulatory Proteins; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D000071186:Beclin-1; D002762:Cholecalciferol; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D025841:Small Ubiquitin-Related Modifier Proteins; D044764:Ubiquitin-Activating Enzymes; D014815:Vitamins; D054804:Cathelicidins; C466624:ATG12 protein, human; C502778:ATG5 protein, human; C491997:BECN1 protein, human; C509349:ATG7 protein, human