Type I Interferon Upregulates Bak and Contributes to T Cell Loss during Human Immunodeficiency Virus (HIV) Infection

PLoS Pathogens

Mark G. Lewis¹  Jeffrey M. Jacobson²  Guibin Yang³  Noshin Kathuria³  Peter D. Katsikis³  Duc H. Do³  Donald T. Gracias³  Jennifer L. Hope³  Joseph A. Fraietta³  Yvonne M. Mueller³  Alina C. Boesteanu³  Luis D. Giavedoni⁴  Shannon E. McGettigan⁵ 

[1] BIOQUAL, Inc., Rockville, Maryland, United States of America;Department of Medicine, Division of Infectious Diseases and HIV Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America;Department of Microbiology and Immunology, Center for Immunology and Vaccine Science, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America;Departments of Virology and Immunology, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, United States of America;Translational Research Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

关键词: T cells;    Apoptosis;    HIV-1;    Cytotoxic T cells;    SIV;    Viral load;    Flow cytometry;    Small interfering RNAs;   

DOI  :  10.1371/journal.ppat.1003658

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The role of Type I interferon (IFN) during pathogenic HIV and SIV infections remains unclear, with conflicting observations suggesting protective versus immunopathological effects. We therefore examined the effect of IFNα/β on T cell death and viremia in HIV infection. Ex vivo analysis of eight pro- and anti-apoptotic molecules in chronic HIV-1 infection revealed that pro-apoptotic Bak was increased in CD4+ T cells and correlated directly with sensitivity to CD95/Fas-mediated apoptosis and inversely with CD4+ T cell counts. Apoptosis sensitivity and Bak expression were primarily increased in effector memory T cells. Knockdown of Bak by RNA interference inhibited CD95/Fas-induced death of T cells from HIV-1-infected individuals. In HIV-1-infected patients, IFNα-stimulated gene expression correlated positively with ex vivo T cell Bak levels, CD95/Fas-mediated apoptosis and viremia and negatively with CD4+ T cell counts. In vitro IFNα/β stimulation enhanced Bak expression, CD95/Fas expression and CD95/Fas-mediated apoptosis in healthy donor T cells and induced death of HIV-specific CD8+ T cells from HIV-1-infected patients. HIV-1 in vitro sensitized T cells to CD95/Fas-induced apoptosis and this was Toll-like receptor (TLR)7/9- and Type I IFN-dependent. This sensitization by HIV-1 was due to an indirect effect on T cells, as it occurred in peripheral blood mononuclear cell cultures but not purified CD4+ T cells. Finally, peak IFNα levels and viral loads correlated negatively during acute SIV infection suggesting a potential antiviral effect, but positively during chronic SIV infection indicating that either the virus drives IFNα production or IFNα may facilitate loss of viral control. The above findings indicate stage-specific opposing effects of Type I IFNs during HIV-1 infection and suggest a novel mechanism by which these cytokines contribute to T cell depletion, dysregulation of cellular immunity and disease progression.

【 授权许可】

CC BY