Dataset Information

Responsiveness to IL-7 but not to IFN-α is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T-cell recovery.

ABSTRACT:

Objective

To assess CD4 T-cell responsiveness to IL-7 and IFN-α in HIV-infected patients who experience poor recovery of CD4 T-cell counts during therapy (immune failure patients).

Design

Responses to IL-7 and IFN-α were compared between HIV-infected immune failure (CD4 cell counts <379 cells/μl) patients and immune success (CD4 cell counts >500 cells/μl) as well as healthy control patients.

Methods

Flow cytometry was used to assess peripheral blood mononuclear cells for IL-7-induced proliferation, CD25 expression, and signaling (signal transducer and activator of transcription 5 phosphorylation and Akt phosphorylation) in CD4 T cells. Freshly isolated cells were characterized by expression of IL-7Rα (CD127) among CD4 T-cell maturation subsets by flow cytometry and sorted CD3 T cells were assessed for expression of IFN-α and interferon stimulated genes (2'-5'-oligoadenylate synthetase-1 and myxovirus resistance A protein) by quantitative real-time PCR. Responses to IFN-α were assessed by induction of signal transducer and activator of transcription 1 phosphorylation and inhibition of IL-7-induced CD4 T-cell proliferation.

Results

IL-7-induced proliferation and CD25 expression were decreased in CD4 T cells from immune failure patients. CD127 expressing CD4 T cells were decreased, whereas expression of 2'-5'-oligoadenylate synthetase-1, myxovirus resistance A protein, and IFN-α mRNA were increased in total CD3 T cells from immune failure patients. CD127 expression correlated with CD25 induction but not proliferation, whereas T-cell IFN-α mRNA was associated with reduced proliferation in CD4 T cells from immune failure patients. IFN-α-mediated induction of signal transducer and activator of transcription 1 phosphorylation and inhibition of proliferation were not diminished in CD4 T cells from immune failure patients.

Conclusion

IL-7 responsiveness is impaired in immune failure patients and may be related to expression of CD127 and IFN-α.

SUBMITTER: Nguyen TP

PROVIDER: S-EPMC5022566 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Publications

Responsiveness to IL-7 but not to IFN-α is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T-cell recovery.

Nguyen Thao P TP Shukla Supriya S Asaad Robert R Freeman Michael L ML Lederman Michael M MM Harding Clifford V CV Sieg Scott F SF

AIDS (London, England) 20160801 13

<h4>Objective</h4>To assess CD4 T-cell responsiveness to IL-7 and IFN-α in HIV-infected patients who experience poor recovery of CD4 T-cell counts during therapy (immune failure patients).<h4>Design</h4>Responses to IL-7 and IFN-α were compared between HIV-infected immune failure (CD4 cell counts <379 cells/μl) patients and immune success (CD4 cell counts >500 cells/μl) as well as healthy control patients.<h4>Methods</h4>Flow cytometry was used to assess peripheral blood mononuclear cells for IL ...[more]

PMID: 27191978

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Project description:The lack of a human immunodeficiency virus (HIV) cure has heightened interest in immunotherapy. As such, type I interferons (IFNs), in particular, IFN alpha (IFN-α), have gained renewed attention. However, HIV pathogenesis is driven by sustained IFN-mediated immune activation, and the use of IFNs is rather controversial. The following questions therein remain: (i) which IFN-α subtype to use, (ii) at which regimen, and (iii) at what time point in HIV infection it might be beneficial. Here, we used IFN-α14 modified by PASylation for its long half-life in vivo to eventually treat HIV infection. We defined the IFN dosing regimen based on the maximum increase in interferon-stimulated gene (ISG) expression 6 h after its administration and a return to baseline of ubiquitin-specific protease 18 (USP18) prior to the next dose. Notably, USP18 is the major negative regulator of type I IFN signaling. HIV infection resulted in increased ISG expression levels in humanized mice. Intriguingly, high baseline ISG levels correlated with lower HIV load. No effect was observed on HIV replication when PASylated IFN-α14 was administered in the chronic phase. However, combined antiretroviral therapy (cART) restored responsiveness to IFN, and PASylated IFN-α14 administered during analytical cART interruption resulted in a transiently lower HIV burden than in the mock-treated mice. In conclusion, cART-mediated HIV suppression restored transient IFN responsiveness and provided a potential window for immunoenhancing therapies in the context of analytical cART interruption. IMPORTANCE cART is highly efficient in suppressing HIV replication in HIV-infected patients and has resulted in a dramatic reduction in morbidity and mortality in HIV-infected people, yet it does not cure HIV infection. In addition, cART has several disadvantages. Thus, the HIV research community is exploring novel ways to control HIV infection for longer periods without cART. Here, we explored novel, long-acting IFN-α14 for its efficacy to control HIV replication in HIV-infected humanized mice. We found that IFN-α14 had no effect on chronic HIV infection. However, when mice were treated first with cART, we observed a transiently restored responsiveness to INF and a transiently lower HIV burden after stopping cART. These data emphasize (i) the value of cART-mediated HIV suppression and immune reconstitution in creating a window of opportunity for exploring novel immunotherapies, (ii) the potential of IFNs for constraining HIV, and (iii) the value of humanized mice for exploring novel immunotherapies.

Dataset Information

Responsiveness to IL-7 but not to IFN-α is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T-cell recovery.

Objective

Design

Methods

Results

Conclusion

Publications

Responsiveness to IL-7 but not to IFN-α is diminished in CD4+ T cells from treated HIV infected patients who experience poor CD4+ T-cell recovery.

Similar Datasets

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