Vitamin D Inhibits Human Immunodeficiency Virus Type 1 and Infection in Macrophages through the Induction of Autophagy

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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.

Vyšlo v časopise: Vitamin D Inhibits Human Immunodeficiency Virus Type 1 and Infection in Macrophages through the Induction of Autophagy. PLoS Pathog 8(5): e32767. doi:10.1371/journal.ppat.1002689
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002689

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Zdroje

1. BezuidenhoutJRobertsTMullerLvan HeldenPWalzlG 2009 Pleural tuberculosis in patients with early HIV infection is associated with increased TNF-alpha expression and necrosis in granulomas. PLoS One 4 e4228

2. de NoronhaALBaficaANogueiraLBarralABarral-NettoM 2008 Lung granulomas from Mycobacterium tuberculosis/HIV-1 co-infected patients display decreased in situ TNF production. Pathol Res Pract 204 155 161

3. LawnSDButeraSTShinnickTM 2002 Tuberculosis unleashed: the impact of human immunodeficiency virus infection on the host granulomatous response to Mycobacterium tuberculosis. Microbes Infect 4 635 646

4. SafiHGormusBJDidierPJBlanchardJLLakeyDL 2003 Spectrum of manifestations of Mycobacterium tuberculosis infection in primates infected with SIV. AIDS Res Hum Retroviruses 19 585 595

5. ShenJYBarnesPFReaTHMeyerPR 1988 Immunohistology of tuberculous adenitis in symptomatic HIV infection. Clin Exp Immunol 72 186 189

6. MartineauARTimmsPMBothamleyGHHanifaYIslamK 2011 High-dose vitamin D(3) during intensive-phase antimicrobial treatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 377 242 250

7. NnoahamKEClarkeA 2008 Low serum vitamin D levels and tuberculosis: a systematic review and meta-analysis. Int J Epidemiol 37 113 119

8. ChanTY 2000 Vitamin D deficiency and susceptibility to tuberculosis. Calcif Tissue Int 66 476 478

9. WejseCOlesenRRabnaPKaestelPGustafsonP 2007 Serum 25-hydroxyvitamin D in a West African population of tuberculosis patients and unmatched healthy controls. Am J Clin Nutr 86 1376 1383

10. WilliamsBWilliamsAJAndersonST 2008 Vitamin D deficiency and insufficiency in children with tuberculosis. Pediatr Infect Dis J 27 941 942

11. MartineauARHoneckerFUWilkinsonRJGriffithsCJ 2007 Vitamin D in the treatment of pulmonary tuberculosis. J Steroid Biochem Mol Biol 103 793 798

12. UstianowskiAShafferRCollinSWilkinsonRJDavidsonRN 2005 Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London. J Infect 50 432 437

13. WilkinsonRJLlewelynMToossiZPatelPPasvolG 2000 Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among Gujarati Asians in west London: a case-control study. Lancet 355 618 621

14. DaviesPDBrownRCWoodheadJS 1985 Serum concentrations of vitamin D metabolites in untreated tuberculosis. Thorax 40 187 190

15. HaugCMullerFAukrustPFrølandSS 1994 Subnormal serum concentration of 1,25-vitamin D in human immunodeficiency virus infection: correlation with degree of immune deficiency and survival. J Infect Dis 169 889 893

16. HaugCJAukrustPHaugEMørkridLMüllerF 1998 Severe deficiency of 1,25-dihydroxyvitamin D3 in human immunodeficiency virus infection: association with immunological hyperactivity and only minor changes in calcium homeostasis. J Clin Endocrinol Metab 83 3832 3838

17. TeichmannJStephanEDischerTLangeUFederlinK 2000 Changes in calciotropic hormones and biochemical markers of bone metabolism in patients with human immunodeficiency virus infection. Metabolism 49 1134 1139

18. TeichmannJStephanELangeUDischerTFrieseG 2003 Osteopenia in HIV-infected women prior to highly active antiretroviral therapy. J Infect 46 221 227

19. MuellerNJFuxCALedergerberBElziLSchmidP 2010 High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS 24 1127 1134

20. ViardJPSouberbielleJCKirkOReekieJKnyszB 2011 Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study. AIDS 25 1305 1315

21. MartineauARNhamoyebondeSOniTRangakaMXMaraisS 2011 Reciprocal seasonal variation in vitamin D status and tuberculosis notifications in Cape Town, South Africa. Proc Natl Acad Sci U S A 108 19013 19017

22. MehtaSGiovannucciEMugusiFMSpiegelmanDAboudS 2010 Vitamin D status of HIV-infected women and its association with HIV disease progression, anemia, and mortality. PLoS One 5 e8770

23. MehtaSHunterDJMugusiFMSpiegelmanDManjiKP 2009 Perinatal outcomes, including mother-to-child transmission of HIV, and child mortality and their association with maternal vitamin D status in Tanzania. J Infect Dis 200 1022 1030

24. CrowleAJRossEJMayMH 1987 Inhibition by 1,25(OH)2-vitamin D3 of the multiplication of virulent tubercle bacilli in cultured human macrophages. Infect Immun 55 2945 2950

25. MartineauARWilkinsonKANewtonSMFlotoRANormanAW 2007 IFN-gamma- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. J Immunol 178 7190 7198

26. RookGASteeleJFraherLBarkerSKarmaliR 1986 Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 57 159 163

27. PauzaCDKornbluthREmauPRichmanDDDeftosLJ 1993 Vitamin D3 compounds regulate human immunodeficiency virus type 1 replication in U937 monoblastoid cells and in monocyte-derived macrophages. J Leukoc Biol 53 157 164

28. CampbellGRSpectorSA 2011 Hormonally active vitamin D3 (1α,25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection. J Biol Chem 286 18890 18902

29. EspertLBiard-PiechaczykM 2009 Autophagy in HIV-induced T cell death. Curr Top Microbiol Immunol 335 307 321

30. ZhouDSpectorSA 2008 Human immunodeficiency virus type-1 infection inhibits autophagy. AIDS 22 695 699

31. BrassALDykxhoornDMBenitaYYanNEngelmanA 2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science 319 921 926

32. KlionskyDJAbeliovichHAgostinisPAgrawalDKAlievG 2008 Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4 151 175

33. MizushimaNYoshimoriT 2007 How to interpret LC3 immunoblotting. Autophagy 3 542 545

34. MizushimaNYamamotoAHatanoMKobayashiYKabeyaY 2001 Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells. J Cell Biol 152 657 668

35. EngKEPanasMDKarlsson HedestamGBMcInerneyGM 2010 A novel quantitative flow cytometry-based assay for autophagy. Autophagy 6 634 641

36. BjorkoyGLamarkTBrechAOutzenHPeranderM 2005 p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171 603 614

37. GalluzziLAaronsonSAAbramsJAlnemriESAndrewsDW 2009 Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ 16 1093 1107

38. YukJMShinDMLeeHMYangCSJinHS 2009 Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe 6 231 243

39. KyeiGBDinkinsCDavisASRobertsESinghSB 2009 Autophagy pathway intersects with HIV-1 biosynthesis and regulates viral yields in macrophages. J Cell Biol 186 255 268

40. LiuPTStengerSTangDHModlinRL 2007 Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 179 2060 2063

41. MartineauAR 2012 Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis. Proc Nutr Soc 71 84 89

42. Lanham-NewSAButtrissJLMilesLMAshwellMBerryJL 2011 Proceedings of the Rank Forum on Vitamin D. Br J Nutr 105 144 156

43. VergneIChuaJSinghSBDereticV 2004 Cell biology of mycobacterium tuberculosis phagosome. Annu Rev Cell Dev Biol 20 367 394

44. GutierrezMGMasterSSSinghSBTaylorGAColomboMI 2004 Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 119 753 766

45. SinghSBDavisASTaylorGADereticV 2006 Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313 1438 1441

46. WelzTChildsKIbrahimFPoultonMTaylorCB 2010 Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 24 1923 1928

47. HolickMF 2007 Vitamin D deficiency. N Engl J Med 357 266 281

48. HagenauTVestRGisselTNPoulsenCSErlandsenM 2009 Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis. Osteoporos Int 20 133 140

49. WangTJZhangFRichardsJBKestenbaumBvan MeursJB 2010 Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376 180 188

50. LiuPTStengerSLiHWenzelLTanBH 2006 Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311 1770 1773

51. FabriMStengerSShinDMYukJMLiuPT 2011 Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med 3 104ra102

52. GartnerSMarkovitsPMarkovitzDMKaplanMHGalloRC 1986 The role of mononuclear phagocytes in HTLV-III/LAV infection. Science 233 215 219

53. PopovicMGartnerSRead-ConnoleEBeaverBReitzM 1988 Cell tropism and expression of HIV-1 isolates in natural targets. GirardMValetteL Retroviruses of Human AIDS and Related Animal Diseases, Colloque Des Cent Gardes; 27–29 October 1988 Marnes-La-Coquette, France Pasteur Vaccins 21 27

54. CampbellGRLoretEPSpectorSA 2010 HIV-1 clade B Tat, but not clade C Tat, increases X4 HIV-1 entry into resting but not activated CD4+ T cells. J Biol Chem 285 1681 1691