Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy

David, D. J.; Keller, H; Naït-Ighil, Lella; Treilhou, Marie-Pierre; Joussemet, M.; Dupont, B.; Gachot, Bertrand; Maral, J; Thèze, Jacques

doi:10.1097/00002030-200205240-00002

Cited by 23 publications

(12 citation statements)

References 26 publications

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“…The fact that CD4 ϩ T cells from HIV-infected individuals are very sensitive to spontaneous and CD95/Fas-induced apoptosis (8), while having normal levels of Bcl-2, whereas Bcl-2 levels correlate with this apoptosis in CD8 ϩ T cells, supports this hypothesis. Our findings showing normal Bcl-2 levels in CD4 ϩ T cells differ from a previous study that showed reduced levels of Bcl-2 in CD4 ϩ T cells from HIV-infected patients (43). This discrepancy, however, may be due to differences in patient populations, as this later study focused on patients that were low responders to highly active antiretroviral therapy.…”

Section: Discussioncontrasting

confidence: 99%

HIV-Specific CD8+ T Cells Exhibit Markedly Reduced Levels of Bcl-2 and Bcl-xL

Petrovas

Mueller

Dimitriou

et al. 2004

The Journal of Immunology

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Human immunodeficiency virus-specific CD8+ T cells are highly sensitive to spontaneous and CD95/Fas-induced apoptosis, and this sensitivity may impair their ability to control HIV infection. To elucidate the mechanism behind this sensitivity, in this study we examined the levels of antiapoptotic molecules Bcl-2 and Bcl-xL in HIV-specific CD8+ T cells from HIV-infected individuals. Bcl-2 expression was markedly decreased in HIV-specific CD8+ T cells compared with CMV-specific and total CD8+ T cells from HIV-infected individuals as well as total CD8+ T cells from healthy donors. CD8+ T cell Bcl-2 levels inversely correlated with spontaneous and CD95/Fas-induced apoptosis of CD8+ T cells from HIV-infected individuals. HIV-specific CD8+ T cells also had significantly lower levels of Bcl-xL compared with CMV-specific CD8+ T cells. Finally, IL-15 induces both Bcl-2 and Bcl-xL expression in HIV-specific and total CD8+ T cells, and this correlated with apoptosis inhibition and increased survival in both short- and long-term cultures. Our data indicate that reduced Bcl-2 and Bcl-xL may play an important role in the increased sensitivity to apoptosis of HIV-specific CD8+ T cells and suggest a possible mechanism by which IL-15 increases their survival.

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Section: Discussioncontrasting

confidence: 99%

HIV-Specific CD8+ T Cells Exhibit Markedly Reduced Levels of Bcl-2 and Bcl-xL

Petrovas

Mueller

Dimitriou

et al. 2004

The Journal of Immunology

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“…A significant inverse correlation was observed between Bak expression and the absolute numbers of CD4+ T cells in HIV-1-infected patients (Figure 2B), whereas Bax and Bim were not associated with CD4+ T cell loss in vivo (Figure 2B). As previously reported in HIV-1-infected patients [28], [30], [32], Bcl-2 was decreased in CD8+ T cells (Table 1). Ex vivo levels of Bid and FADD in CD4+ T cells and CD8+ T cells did not differ between healthy donors and HIV-1-infected individuals (Table 1).…”

Section: Resultssupporting

confidence: 86%

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

et al. 2013

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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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“…This suggests that inflammation may be driving decreased CD127 expression and inhibiting responsiveness to IL-7 and CD4 recovery in immune failure as suggested earlier by our in vitro studies where both IL-1β and IL-6 decreased CD127 expression and these cytokines as well as type 1 interferon could impair IL-7 responsiveness [18, 26]. Other studies have demonstrated that T cells from immune failure patients show reduced proliferation [11, 12] and fail to up-regulate Bcl2 [11, 12, 38] in response to IL-7. Here, we saw significantly lower proportions of Bcl2 positive CD4 T cells in immune failure, but in vitro responses to IL-7 were not examined.…”

Section: Discussionsupporting

confidence: 65%

“…Reduced levels of the pro-survival factor Bcl2 have been found in CD4 T cells from viremic HIV-infected patients [11] and immune failure patients [38], and CD4 T cells from these patients have a reduced ability to increase Bcl2 after IL-7 stimulation [11, 24]. Most CD4 T cells expressed detectable levels of Bcl2, ranging from 88%-98% in healthy controls, 89%-98% in immune success patients, and 81%-98% in immune failure patients; however the median proportion of Bcl2+ CD4 T cells was lower in immune failure patients (92%) than among healthy controls (97%, p = <0.0001) or among immune success patients (96%, p= 0.0006) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection

Shive

Clagett

McCausland

et al. 2016

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background HIV-infected patients who fail to normalize CD4 T cells despite suppressive antiretroviral therapy have impaired immune homeostasis: diminished naïve T cell numbers, elevated T cell turnover, senescence and inflammation. Methods Blood samples from immune failures (n=60), immune successes (n=20) and healthy controls (n=20) were examined for plasma IL-7 levels, for cellular expression of the IL-7Rα chain (CD127), for the exhaustion and senescence markers PD-1 and CD57, and for the survival factor Bcl2. As both inflammatory and homeostatic cytokines can induce T cell cycling, we also examined the effects of these mediators on exhaustion and senescence markers. Results Plasma levels of IL-7 were elevated and both CD4 and CD8 T cell CD127 expression was decreased in immune failure. Plasma levels of IL-7 correlated directly with naïve CD4 T cell counts in immune success and inversely with T cell cycling (Ki67) in healthy controls and immune success, but not in immune failure. CD4 T cell density of PD-1 was increased and Bcl2+ CD4 T cells were decreased in immune failure but not in immune success, while the proportion of T cells expressing CD57 was increased in immune failure. PD-1 and CD57 were induced on CD4 but not CD8 T cells by stimulation in vitro with inflammatory (IL-1β) or homeostatic (IL-7) cytokines. Conclusions Perturbation of the IL-7/IL-7 receptor axis, increased T cell turnover, and increased senescence may reflect dysregulated responses to both homeostatic and inflammatory cytokines in immune failure patients.

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Involvement of Bcl-2 and IL-2R in HIV-positive patients whose CD4 cell counts fail to increase rapidly with highly active antiretroviral therapy

Abstract: Our study characterizes the defective maintenance of peripheral CD4 T lymphocytes in CD4-LR patients, probably resulting from Bcl-2 underexpression and dysregulation of the IL-2R system.

Cited by 23 publications

References 26 publications

HIV-Specific CD8+ T Cells Exhibit Markedly Reduced Levels of Bcl-2 and Bcl-xL

HIV-Specific CD8+ T Cells Exhibit Markedly Reduced Levels of Bcl-2 and Bcl-xL

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

Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection

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