Regulatory Dysfunction of the Interleukin-7 Receptor in CD4 and CD8 Lymphocytes From HIV-Infected Patients-Effects of Antiretroviral Therapy

Colle, Jean-Herv??; Moreau, Jean‐Louis; Fontanet, Arnaud; Lambotte, Olivier; Joussemet, M.; Jacod, Sylvie; Delfraissy, Jean-Fran??ois; Th??ze, Jacques

doi:10.1097/01.qai.0000218350.75346.37

Cited by 20 publications

(45 citation statements)

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“…Indeed, the increase seen in plasma IL-7 levels in HIV-infected subjects is far lower than the dose of rIL-7 that was recently administered to humans [7]. The second is that the IL-7/IL-7 receptor axis may be impaired [12]. Our data supported the notion that CD127 expression was progressively lost during chronic HIV infection and might lead to poor responsiveness to IL-7 and increased apoptosis of T cells.…”

Section: Discussionsupporting

confidence: 77%

“…This inability of plasma IL-7 to reverse the loss of CD4 T cells in vivo during the course of HIV-1 infection is still poorly understood. An alternative explanation is that the IL-7/CD127 axis may be impaired during HIV infection [12]. Actually, the IL-7 receptor, CD127, is an essential subunit for IL-7 signaling.…”

Section: Introductionmentioning

confidence: 99%

“…Actually, the IL-7 receptor, CD127, is an essential subunit for IL-7 signaling. In parallel with an increased IL-7 level in plasma, CD127 expression on T cells was significantly down-regulated and correlated with HIV-1 disease progression [12,13]. Until now, little has been known regarding the underlying mechanisms of CD127 loss and the resulting immunological consequences during HIV infection, in particular, the role of CD127 in T-cell apoptosis in this disease.…”

Section: Introductionmentioning

confidence: 99%

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Progressive CD127 down‐regulation correlates with increased apoptosis of CD8 T cells during chronic HIV‐1 infection

Zhang

et al. 2009

Eur J Immunol

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Chronic HIV‐1 infection can induce a significant decrease in CD127 expression on CD8 T cells, but the underlying mechanisms and immunological consequences are unclear. In this study, we investigated CD127 expression on CD8 T cells from a total of 51 HIV‐1‐infected subjects and 16 healthy individuals and analyzed the association between CD127 expression and CD8 T‐cell apoptosis in these HIV‐1‐infected subjects. We found that CD127 expression on total CD8 T cells was significantly down‐regulated, which was correlated with the increased CD8 T‐cell apoptosis and disease progression of chronic HIV‐1 infection. The in vitro addition of IL‐7 efficiently rescued the spontaneous apoptosis of CD8 T cells from HIV‐1‐infected individuals. IL‐7 stimulation also transiently down‐regulated CD127 expression, whereas some of the CD127− CD8 T cells regained CD127 expression soon after IL‐7 was retracted from the incubation medium. Thus, IL‐7 stimulation reduced apoptosis of both CD127+ and CD127−CD8 T cells to some degree. These data indicate that CD127 loss might impair IL‐7 signaling and increase CD8 T‐cell apoptosis during HIV‐1 infection. This study, therefore, will extend the notion that IL‐7 could be a good candidate for immunotherapy in HIV‐1‐infected patients.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Progressive CD127 down‐regulation correlates with increased apoptosis of CD8 T cells during chronic HIV‐1 infection

Zhang

et al. 2009

Eur J Immunol

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“…HIV-infected patients have lower expression levels of cell surface IL-7R␣ and higher levels of ␥ c on their CD4 and CD8 T lymphocytes than healthy individuals (27)(28)(29). In addition, they frequently show increased plasma IL-7 concentrations (12).…”

Section: Plasma Sil-7r␣-chain Concentrations Are Lower In Chronicallymentioning

confidence: 99%

Identification and Biochemical Characterization of Human Plasma Soluble IL-7R: Lower Concentrations in HIV-1-Infected Patients

Rose

Lambotte

Pallier

et al. 2009

The Journal of Immunology

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The IL-7R α-chain and the common γ-chain (γc) are both components of IL-7R. Human plasma harbors soluble forms of IL-7R (sIL-7Rα and sγc) that are detected and assayed by Western blotting, showing that the levels of sIL-7Rα are higher than the levels of sγc (47.5 ng/ml and 1.5 ng/ml, respectively). Gel electrophoresis and tandem mass spectrometry used to analyze deglycosylated, affinity-purified protein showed that sIL-7Rα is generated through differentially spliced mRNA, not by membrane receptor shedding. Plasma sIL-7Rα and sγc are present as heterocomplexes and sγc was found to be mainly associated with sIL-7Rα. The affinities of two IL-7 binding sites (Kd = 35 ± 8 pM and Kd = 3 ± 1 nM) were similar to that of the membrane receptor, suggesting that the sIL-7Rα/sγc complex retains high affinity for IL-7. sIL-7Rα mRNA is constitutively present among peripheral T lymphocytes and is down-modulated in vitro by IL-7. Chronically HIV-1-infected patients (n = 20) showed no significant (p > 0.714) variation in sγc levels and a significant (p < 0.0014) 2-fold decrease in plasma sIL-7Rα levels compared with those in control healthy individuals. Plasma IL-7 and sIL-7Rα levels did not show any obvious relationship.

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“…12,13 Previous studies have found that impaired IL-7 responsiveness is significantly associated with poor CD4 T-cell recovery following cART. 14,15 Various clinical factors have been associated with impaired CD4 T-cell reconstitution following cART, including lower CD4 T-cell counts at initiation of cART, [16][17][18][19] being older at cART initiation 1,17,19,20 and higher levels of immune activation both before and while on cART as measured by T-cell activation markers (such as human leukocyte antigen (HLA)-DR þ CD38 þ expression). [21][22][23][24] Multiple host genetic factors have also been found to influence CD4 T-cell recovery.…”

Section: Introductionmentioning

confidence: 99%

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

et al. 2011

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We previously found an association between faster CD4 þ T-cell recovery in HIV-infected patients receiving combination antiretroviral therapy (cART) and interleukin-7 receptor-a (IL-7Ra) haplotype-2 in a predominantly Caucasian cohort. This study aims to determine whether this association was also significant in Africans. Patients were recruited from the Uganda AIDS Rural Treatment Outcomes (UARTO) cohort (n ¼ 352). We used survival analysis and linear mixed modelling (LMM) to determine factors associated with CD4 T-cell recovery. Eight IL-7Ra single-nucleotide polymorphisms (SNPs) were genotyped in both Africans and Caucasians (n ¼ 57). Soluble (s)IL-7Ra levels were measured by ELISA. In UARTO, IL-7Ra haplotype-2 was associated with slower CD4 T-cell recovery following cART by using survival analysis (P ¼ 0.020) and no association was found with LMM (P ¼ 0.958). The tagging-SNP for IL-7Ra haplotype-2 (rs6897932) was associated with decreased sIL-7Ra (Po0.001). The haplotypes for the IL-7Ra were significantly different in Africans and Caucasians. Using IL-7Ra genotypes we found slower CD4 T-cell recovery in UARTO patients was still associated with rs6897932 (P ¼ 0.009) and rs3194051 was associated with faster CD4 T-cell recovery (P ¼ 0.006). Unlike Caucasians, we did not demonstrate a significant association between IL-7Ra haplotype 2 and faster CD4 T-cell recovery in Africans. The IL-7Ra SNPs associated with CD4 T-cell recovery following cART differ in African and Caucasian cohorts.

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Regulatory Dysfunction of the Interleukin-7 Receptor in CD4 and CD8 Lymphocytes From HIV-Infected Patients-Effects of Antiretroviral Therapy

Cited by 20 publications

References 0 publications

Progressive CD127 down‐regulation correlates with increased apoptosis of CD8 T cells during chronic HIV‐1 infection

Progressive CD127 down‐regulation correlates with increased apoptosis of CD8 T cells during chronic HIV‐1 infection

Identification and Biochemical Characterization of Human Plasma Soluble IL-7R: Lower Concentrations in HIV-1-Infected Patients

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

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