title: Vitamin D inhibits human immunodeficiency virus type 1 and Mycobacterium tuberculosis infection in macrophages through the induction of autophagy.
abstract: Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We have previously shown that 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits HIV replication in human macrophages through the induction of autophagy. In this study, we report that physiological concentrations of 1,25D3 induce the production of the human cathelicidin microbial peptide (CAMP) and autophagic flux in HIV and M. tuberculosis co-infected human macrophages which inhibits mycobacterial growth and the replication of HIV. Using RNA interference for Beclin-1 and the autophagy-related 5 homologue, combined with the chemical inhibitors of autophagic flux, bafilomycin A₁, an inhibitor of autophagosome-lysosome fusion and subsequent acidification, and SID 26681509 an inhibitor of the lysosome hydrolase cathepsin L, we show that the 1,25D3-mediated inhibition of HIV replication and mycobacterial growth during single infection or dual infection is dependent not only upon the induction of autophagy, but also through phagosomal maturation. Moreover, through the use of RNA interference for CAMP, we demonstrate that cathelicidin is essential for the 1,25D3 induced autophagic flux and inhibition of HIV replication and mycobacterial growth. The present findings provide a biological explanation for the benefits and importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections.
authors.affiliation: Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Campbell
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Spector
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002112:Calcifediol / Q000494:pharmacology*; D002478:Cells, Cultured; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000382:microbiology / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D010588:Phagosomes / Q000187:drug effects / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy / Q000517:prevention & control; D054804:Cathelicidins
chemical_list: C502778:ATG5 protein, human; D023181:Antimicrobial Cationic Peptides; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D006834:Hydrazines; D018942:Macrolides; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C576116:SID 26681509; C040929:bafilomycin A1; D013890:Thiourea; D002112:Calcifediol; D054804:Cathelicidins