Attenuation of Pathogenic Immune Responses during Infection with Human and Simian Immunodeficiency Virus HIV-SIV by the Tetracycline Derivative MinocyclineReportar como inadecuado




Attenuation of Pathogenic Immune Responses during Infection with Human and Simian Immunodeficiency Virus HIV-SIV by the Tetracycline Derivative Minocycline - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Julia L. Drewes, Gregory L. Szeto, Elizabeth L. Engle, Zhaohao Liao, Gene M. Shearer, M. Christine Zink , David R. Graham

Fuente: http://plos.srce.hr/



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