Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.
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-...
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2013
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oai:doaj.org-article:f681ebe2086b4e1387218826ddfdc7cf2021-11-18T06:07:31ZType I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.1553-73661553-737410.1371/journal.ppat.1003658https://doaj.org/article/f681ebe2086b4e1387218826ddfdc7cf2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24130482/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The 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.Joseph A FraiettaYvonne M MuellerGuibin YangAlina C BoesteanuDonald T GraciasDuc H DoJennifer L HopeNoshin KathuriaShannon E McGettiganMark G LewisLuis D GiavedoniJeffrey M JacobsonPeter D KatsikisPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 10, p e1003658 (2013) |
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DOAJ |
| collection |
DOAJ |
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| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Joseph A Fraietta Yvonne M Mueller Guibin Yang Alina C Boesteanu Donald T Gracias Duc H Do Jennifer L Hope Noshin Kathuria Shannon E McGettigan Mark G Lewis Luis D Giavedoni Jeffrey M Jacobson Peter D Katsikis Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. |
| description |
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. |
| format |
article |
| author |
Joseph A Fraietta Yvonne M Mueller Guibin Yang Alina C Boesteanu Donald T Gracias Duc H Do Jennifer L Hope Noshin Kathuria Shannon E McGettigan Mark G Lewis Luis D Giavedoni Jeffrey M Jacobson Peter D Katsikis |
| author_facet |
Joseph A Fraietta Yvonne M Mueller Guibin Yang Alina C Boesteanu Donald T Gracias Duc H Do Jennifer L Hope Noshin Kathuria Shannon E McGettigan Mark G Lewis Luis D Giavedoni Jeffrey M Jacobson Peter D Katsikis |
| author_sort |
Joseph A Fraietta |
| title |
Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. |
| title_short |
Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. |
| title_full |
Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. |
| title_fullStr |
Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. |
| title_full_unstemmed |
Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection. |
| title_sort |
type i interferon upregulates bak and contributes to t cell loss during human immunodeficiency virus (hiv) infection. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/f681ebe2086b4e1387218826ddfdc7cf |
| work_keys_str_mv |
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