IL-7 administration drives T cell–cycle entry and expansion in HIV-1 infection (original) (raw)
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Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment
Journal of Clinical Investigation, 2009
In a prospective openlabel phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART-treated HIV-infected patients whose CD4 + cell counts were between 100 and 400 cells/μl and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 μg/kg) 3 times per week over a 16-day period.
Journal of Virology, 2007
Proliferation responses of naïve CD4 ؉ T cells to T-cell receptor and interleukin-7 (IL-7) stimulation were evaluated by using cells from human immunodeficiency virus-positive (HIV ؉ ) donors. IL-7 enhanced responses to T-cell receptor stimulation, and the magnitude of this enhancement was similar in cells from healthy controls and from HIV ؉ subjects. The overall response to T-cell receptor stimulation alone or in combination with IL-7, however, was diminished among viremic HIV ؉ donors and occurred independent of antigen-presenting cells. Frequencies of CD127 ؉ cells were related to the magnitudes of proliferation enhancement that were mediated by IL-7. Thus, IL-7 enhances but does not fully restore the function of naïve CD4 ؉ T cells from HIV-infected persons.
The Journal of Infectious Diseases, 2014
Background. Systemic inflammation has been linked to a failure to normalize CD4 + T-cell numbers in treated human immunodeficiency virus (HIV) infection. Although inflammatory cytokines such as interleukin 6 (IL-6) are predictors of disease progression in treated HIV infection, it is not clear how or whether inflammatory mediators contribute to immune restoration failure. Methods. We examined the in vitro effects of IL-6 and interleukin 1β (IL-1β) on peripheral blood T-cell cycling and CD127 surface expression. Results. The proinflammatory cytokine IL-1β induces cell cycling and turnover of memory CD4 + T cells, and IL-6 can induce low-level cycling of naive T cells. Both IL-1β and IL-6 can decrease T-cell surface expression and RNA levels of CD127, the interleukin 7 receptor α chain (IL-7Rα). Preexposure of healthy peripheral blood mononuclear cells (PBMCs) to IL-6 or IL-1β attenuates IL-7-induced Stat5 phosphorylation and induction of the prosurvival factor Bcl-2 and the gut homing integrin α4β7. We found elevated expression of IL-1β in the lymphoid tissues of patients with HIV infection that did not normalize with antiretroviral therapy. Conclusions. Induction of CD4 + T-cell turnover and diminished T-cell responsiveness to IL-7 by IL-1β and IL-6 exposure may contribute to the lack of CD4 + T-cell reconstitution in treated HIV-infected subjects.
Blood, 2011
IL-7 is essential for T-cell homeostasis. Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV+ patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling. Immunophenotypic analysis of T cells from 29 HIV− controls and 43 untreated HIV+ patients (30 of whom were followed longitudinally for ≤ 24 months on ART) was performed. Restoration of both CD4+ and CD8+ T cells was driven by increases in CD127+ naive and central memory T cells. CD4+ T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest t...
Quantifying and Predicting the Effect of Exogenous Interleukin-7 on CD4+T Cells in HIV-1 Infection
PLoS Computational Biology, 2014
Exogenous Interleukin-7 (IL-7), in supplement to antiretroviral therapy, leads to a substantial increase of all CD4 + T cell subsets in HIV-1 infected patients. However, the quantitative contribution of the several potential mechanisms of action of IL-7 is unknown. We have performed a mathematical analysis of repeated measurements of total and naive CD4 + T cells and their Ki67 expression from HIV-1 infected patients involved in three phase I/II studies (N = 53 patients). We show that, besides a transient increase of peripheral proliferation, IL-7 exerts additional effects that play a significant role in CD4 + T cell dynamics up to 52 weeks. A decrease of the loss rate of the total CD4 + T cell is the most probable explanation. If this effect could be maintained during repeated administration of IL-7, our simulation study shows that such a strategy may allow maintaining CD4 + T cell counts above 500 cells/mL with 4 cycles or fewer over a period of two years. This in-depth analysis of clinical data revealed the potential for IL-7 to achieve sustained CD4 + T cell restoration with limited IL-7 exposure in HIV-1 infected patients with immune failure despite antiretroviral therapy.
PLoS ONE, 2010
Background: The bone marrow (BM) cytokine milieu might substantially affect T-lymphocyte homeostasis in HIV-positive individuals. Interleukin-7 (IL-7) is a bone marrow-derived cytokine regulating T-cell homeostasis through a CD4+-driven feedback loop. CD4+ T-lymphopenia is associated with increased free IL-7 levels and reduced IL-7R expression/function, which are only partially reverted by highly active antiretroviral therapy (HAART). We investigated the BM production, peripheral expression and signaling (pStat5+ and Bcl-2+ CD4+/CD8+ T cells) of IL-7/IL-7Ra in 30 HAART-treated HIV-positive patients who did not experience CD4+ recovery (CD4+ #200/ml) and who had different levels of HIV viremia; these patients included 18 immunological nonresponders (INRs; HIV-RNA#50), 12 complete failures (CFs; HIV-RNA.1000), and 23 HIVseronegative subjects.
HIV Clinical Trials, 2001
Introduction: In response to the human immunodeficiency virus (HIV) infection, activated immune cells produce several cytokines that alter the immune response and HIV disease progression. We quantified Th1/Th2/Th17 cytokines in an antiretroviral therapy naïve (ART) cohort to investigate their correlation with traditional markers of HIV disease progression; CD4+ T-lymphocytes and virus load (VL). Methods: We enrolled 247 HIV-infected ART-naïve participants into the study. CD4+ T-and CD8+ T-lymphocytes were enumerated using flow cytometry. VL was quantified using the Cavidi ExaVir TM Load assay. IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ levels were quantified using the BD Cytometric Bead Array Human Th1/Th2/Th17 cytokine assay. The Kendall's rank correlation coefficient was used to determine the correlation between log 10 transformed data for cytokine levels and CD4+ T-and CD8+ T-lymphocytes, CD4/CD8 ratio, and VL. Results: The median CD4+ T-and CD8+ T-lymphocyte counts were 458 cells/µL (IQR:405-556) and 776 cells/µL (IQR:581-1064), respectively. The median CD4/CD8 ratio was 0.6 (IQR: 0.45-0.86). The median VL was log 10 3.3.copies/mL (IQR:2.74-3.93). Low CD4+ T-lymphocyte counts (p=0.010) and CD4/CD8 ratio (p=0.044) were significantly correlated with high VL. There was no significant correlation of cytokine levels with CD4+ T-, CD8+ T-lymphocyte counts and CD4/CD8 ratio. However, high levels of IL-17A (p=0.012) and IL-6 (p=0.034) were significantly correlated with high VL. Conclusion: Our study contributes to the little knowledge available on the role of cytokine profiles in the immune response to subtype C HIV infection.
AIDS, 2007
The replicative potential of HIV-1 strains in a wellcharacterized group of eight HIV controllers was investigated. Replication-competent viruses were detected in CD4 T-cell co-culture supernatants from all HIV controllers. The phylogenetic analysis of C2V4 suggested viral evolution or co-infection or superinfection in two out of the four patients analysed. The vif and vpr genes were normal. Infection with HIV-1 variants with attenuated replicative capacity cannot be a general factor accounting for undetectable viraemia in HIV controllers.