title: Attenuation of pathogenic immune responses during infection with human and simian immunodeficiency virus (HIV/SIV) by the tetracycline derivative minocycline.
abstract: HIV immune pathogenesis is postulated to involve two major mechanisms: 1) chronic innate immune responses that drive T cell activation and apoptosis and 2) induction of immune regulators that suppress T cell function and proliferation. Both arms are elevated chronically in lymphoid tissues of non-natural hosts, which ultimately develop AIDS. However, these mechanisms are not elevated chronically in natural hosts of SIV infection that avert immune pathogenesis despite similarly high viral loads. In this study we investigated whether minocycline could modulate these pathogenic antiviral responses in non-natural hosts of HIV and SIV. We found that minocycline attenuated in vitro induction of type I interferon (IFN) and the IFN-stimulated genes indoleamine 2,3-dioxygenase (IDO1) and TNF-related apoptosis inducing ligand (TRAIL) in human plasmacytoid dendritic cells and PBMCs exposed to aldrithiol-2 inactivated HIV or infectious influenza virus. Activation-induced TRAIL and expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in isolated CD4+ T cells were also reduced by minocycline. Translation of these in vitro findings to in vivo effects, however, were mixed as minocycline significantly reduced markers of activation and activation-induced cell death (CD25, Fas, caspase-3) but did not affect expression of IFNβ or the IFN-stimulated genes IDO1, FasL, or Mx in the spleens of chronically SIV-infected pigtailed macaques. TRAIL expression, reflecting the mixed effects of minocycline on activation and type I IFN stimuli, was reduced by half, but this change was not significant. These results show that minocycline administered after infection may protect against aspects of activation-induced cell death during HIV/SIV immune disease, but that in vitro effects of minocycline on type I IFN responses are not recapitulated in a rapid progressor model in vivo.
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Julia L
authors.initials: JL
authors.lastname: Drewes
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Szeto
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Engle
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Zhaohao
authors.initials: Z
authors.lastname: Liao
authors.affiliation: Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Gene M
authors.initials: GM
authors.lastname: Shearer
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: M Christine
authors.initials: MC
authors.lastname: Zink
authors.affiliation: Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Johns Hopkins Bayview Proteomics Center, Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine Bayview Campus, Baltimore, Maryland, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Graham
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000378:metabolism; D002469:Cell Separation; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000235:genetics; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D007370:Interferon Type I / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008254:Macaca nemestrina / Q000276:immunology / Q000821:virology; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013752:Tetracycline / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D044966:Anti-Retroviral Agents; D060908:CTLA-4 Antigen; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007370:Interferon Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; D013752:Tetracycline; D008911:Minocycline
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