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Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.

Fraietta JA, Mueller YM, Yang G, Boesteanu AC, Gracias DT, Do DH, Hope JL, Kathuria N, McGettigan SE, Lewis MG, Giavedoni LD, Jacobson JM, Katsikis PD - PLoS Pathog. (2013)

Bottom Line: We therefore examined the effect of IFNα/β on T cell death and viremia in HIV infection.Apoptosis sensitivity and Bak expression were primarily increased in effector memory T cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Center for Immunology and Vaccine Science, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
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.

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CD95/Fas-mediated, but not TRAIL- or TNFα-induced T cell apoptosis is increased in HIV-1-infected individuals and correlates inversely with CD4+ T cell counts.(A) Representative flow cytometry plots depicting apoptosis of CD4+ T cells and HIV-specific CD8+ T cells induced by anti-CD95/Fas antibody, SuperKiller TRAIL or TNFα treated PBMC from HIV-1+ individuals for 14 hours. (B) Pooled data showing percent apoptosis of CD4+ T cells (n = 8), total CD8+ T cells (n = 8), HIV-specific (n = 5) and CMV/EBV-specific (n = 5) CD8+ T cells after anti-CD95/Fas-, TRAIL-, and TNFα-treatment. Bars depict means ± standard errors. The P values were calculated using Student t test for paired samples. (C) Spearman's rho correlation shown between the frequency of CD95/Fas-mediated apoptosis of CD4+ T cells and absolute CD4+ T cell counts (n = 31).
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ppat-1003658-g001: CD95/Fas-mediated, but not TRAIL- or TNFα-induced T cell apoptosis is increased in HIV-1-infected individuals and correlates inversely with CD4+ T cell counts.(A) Representative flow cytometry plots depicting apoptosis of CD4+ T cells and HIV-specific CD8+ T cells induced by anti-CD95/Fas antibody, SuperKiller TRAIL or TNFα treated PBMC from HIV-1+ individuals for 14 hours. (B) Pooled data showing percent apoptosis of CD4+ T cells (n = 8), total CD8+ T cells (n = 8), HIV-specific (n = 5) and CMV/EBV-specific (n = 5) CD8+ T cells after anti-CD95/Fas-, TRAIL-, and TNFα-treatment. Bars depict means ± standard errors. The P values were calculated using Student t test for paired samples. (C) Spearman's rho correlation shown between the frequency of CD95/Fas-mediated apoptosis of CD4+ T cells and absolute CD4+ T cell counts (n = 31).

Mentions: We and others have previously reported that T cells from HIV-1-infected individuals are highly susceptible to CD95/Fas-induced apoptosis [5], [6], [7], [27], [28], [29]. However, the role of other TNF receptor family members in mediating increased T cell death in HIV-1-infected individuals is not well characterized. To address this, we examined the effects of TNFα and TRAIL on the survival of total CD4+ T cells, CD8+ T cells, as well as HIV-, CMV- and EBV-specific CD8+ T cells from HIV-1-infected patients. PBMC from HIV-1-infected subjects were incubated with media alone or with anti-CD95 antibody, TNFα or TRAIL for 14 hours and subsequently stained for apoptosis. While total CD4+ T cells, CD8+ T cells, HIV-specific and CMV/EBV-specific CD8+ T cells were susceptible to CD95/Fas-induced apoptosis (Figure 1A and B), neither TNFα nor TRAIL increased apoptosis above levels of spontaneous death (Figure 1A and B). In contrast, treatment of Jurkat T cells with anti-CD95/Fas antibody, SuperKiller TRAIL alone or TNFα with cyclohexamide induced similar apoptosis levels (data not shown). Furthermore, the enhanced susceptibility of CD4+ T cells to CD95/Fas-mediated death was strongly associated with CD4+ T cell loss in patients (Figure 1C). These in vitro data suggest that CD95/Fas is a predominant apoptotic pathway of the TNF receptor family in HIV-1 disease which contributes to the depletion of CD4+ T cells and impairs cytotoxic T cells.


Type I interferon upregulates Bak and contributes to T cell loss during human immunodeficiency virus (HIV) infection.

Fraietta JA, Mueller YM, Yang G, Boesteanu AC, Gracias DT, Do DH, Hope JL, Kathuria N, McGettigan SE, Lewis MG, Giavedoni LD, Jacobson JM, Katsikis PD - PLoS Pathog. (2013)

CD95/Fas-mediated, but not TRAIL- or TNFα-induced T cell apoptosis is increased in HIV-1-infected individuals and correlates inversely with CD4+ T cell counts.(A) Representative flow cytometry plots depicting apoptosis of CD4+ T cells and HIV-specific CD8+ T cells induced by anti-CD95/Fas antibody, SuperKiller TRAIL or TNFα treated PBMC from HIV-1+ individuals for 14 hours. (B) Pooled data showing percent apoptosis of CD4+ T cells (n = 8), total CD8+ T cells (n = 8), HIV-specific (n = 5) and CMV/EBV-specific (n = 5) CD8+ T cells after anti-CD95/Fas-, TRAIL-, and TNFα-treatment. Bars depict means ± standard errors. The P values were calculated using Student t test for paired samples. (C) Spearman's rho correlation shown between the frequency of CD95/Fas-mediated apoptosis of CD4+ T cells and absolute CD4+ T cell counts (n = 31).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3795023&req=5

ppat-1003658-g001: CD95/Fas-mediated, but not TRAIL- or TNFα-induced T cell apoptosis is increased in HIV-1-infected individuals and correlates inversely with CD4+ T cell counts.(A) Representative flow cytometry plots depicting apoptosis of CD4+ T cells and HIV-specific CD8+ T cells induced by anti-CD95/Fas antibody, SuperKiller TRAIL or TNFα treated PBMC from HIV-1+ individuals for 14 hours. (B) Pooled data showing percent apoptosis of CD4+ T cells (n = 8), total CD8+ T cells (n = 8), HIV-specific (n = 5) and CMV/EBV-specific (n = 5) CD8+ T cells after anti-CD95/Fas-, TRAIL-, and TNFα-treatment. Bars depict means ± standard errors. The P values were calculated using Student t test for paired samples. (C) Spearman's rho correlation shown between the frequency of CD95/Fas-mediated apoptosis of CD4+ T cells and absolute CD4+ T cell counts (n = 31).
Mentions: We and others have previously reported that T cells from HIV-1-infected individuals are highly susceptible to CD95/Fas-induced apoptosis [5], [6], [7], [27], [28], [29]. However, the role of other TNF receptor family members in mediating increased T cell death in HIV-1-infected individuals is not well characterized. To address this, we examined the effects of TNFα and TRAIL on the survival of total CD4+ T cells, CD8+ T cells, as well as HIV-, CMV- and EBV-specific CD8+ T cells from HIV-1-infected patients. PBMC from HIV-1-infected subjects were incubated with media alone or with anti-CD95 antibody, TNFα or TRAIL for 14 hours and subsequently stained for apoptosis. While total CD4+ T cells, CD8+ T cells, HIV-specific and CMV/EBV-specific CD8+ T cells were susceptible to CD95/Fas-induced apoptosis (Figure 1A and B), neither TNFα nor TRAIL increased apoptosis above levels of spontaneous death (Figure 1A and B). In contrast, treatment of Jurkat T cells with anti-CD95/Fas antibody, SuperKiller TRAIL alone or TNFα with cyclohexamide induced similar apoptosis levels (data not shown). Furthermore, the enhanced susceptibility of CD4+ T cells to CD95/Fas-mediated death was strongly associated with CD4+ T cell loss in patients (Figure 1C). These in vitro data suggest that CD95/Fas is a predominant apoptotic pathway of the TNF receptor family in HIV-1 disease which contributes to the depletion of CD4+ T cells and impairs cytotoxic T cells.

Bottom Line: We therefore examined the effect of IFNα/β on T cell death and viremia in HIV infection.Apoptosis sensitivity and Bak expression were primarily increased in effector memory T cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Center for Immunology and Vaccine Science, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus