Interleukin‐7 levels may predict virological response in advanced HIV‐1‐infected patients receiving lopinavir/ritonavir‐based therapy

Abstract

ObjectivesTo examine the relationship between levels of the T-cell regulatory cytokine interleukin-7 (IL-7) and CD4 cell counts during immune reconstitution and to assess its prognostic value in advanced HIV-1-infected patients receiving lopinavir/ritonavir-based therapy. MethodsThirty-six HIV-1-infected adults who completed 48 weeks of follow-up visits were included in this prospective study. Patients having failed two or more antiretroviral therapy regimens were treated with lopinavir/ritonavir-based therapy. An enzyme-linked immunosorbent assay was used to determine IL-7 plasma levels, flow cytometry was used to analyse cell surface antigens, and polymerase chain reaction was used to quantify plasma HIV-1. ResultsPretreatment IL-7 levels were elevated in all patients (mean 11.0 pg/mL) and were negatively correlated with CD4 cell counts and age (r 5 À 0.59, Po0.001 and r 5 À 0.57, Po0.001, respectively). During the course of treatment, IL-7 levels decreased by 34% while CD4 cell numbers progressively increased by 88%. Multivariate regression analysis showed that only pretreatment IL-7 levels predicted viral load at 48 weeks when controlling for baseline CD4 cell counts, viral load and patient demographics. ConclusionsThese findings are consistent with regulation of T-cell recovery by IL-7, and suggest that IL-7 measurements might be used to predict virological response. IntroductionThe goal of highly active antiretroviral therapy (HAART) is to suppress HIV-1 replication, thereby permitting a restoration of CD4 cell counts. However, CD4 cell reconstitution is often only partial, and CD4 cell counts rarely return to normal values [1]. The reasons for this incomplete reconstitution are unknown. One possibility is inadequate levels or function of T-cell cytokines and/or growth hormones, as T-cell production is regulated by several cytokines and growth hormones that stimulate the maturation, differentiation and survival of T cells [2,3]. Interleukin-7 (IL-7) is one such cytokine crucial for the thymic production of naive T cells and the survival of mature T cells in blood and lymph nodes. In contrast to other type 1 cytokines, such as IL-2 and IL-4, which are produced mainly by T cells and macrophages, IL-7 is derived from thymic, lymph node and bone marrow epithelial and stromal cells [4]. Because of its particular sites of synthesis and its specific role in lymphopoeisis, IL-7 is considered a master regulator of T-cell homeostasis.T-cell depletion resulting from chemotherapy and bone marrow transplantation is associated with an increase in 315 the level of IL-7 and an increase in the regeneration and expansion of T cells [5]. In addition, elevated IL-7 levels have been observed in HIV-1-infected adults with low CD4 cell counts [6][7][8]. However, few reports have been published regarding changes in IL-7 levels following CD4 reconstitution in advanced HIV-1-infected subjects. In the current study, we examined the associations amongst IL-7 levels, CD4 cell counts and viral replication, over 48 weeks in a cohort of...

Persistent human immunodeficiency virus-1 antigenaemia affects the expression of interleukin-7Rα on central and effector memory CD4+ and CD8+ T cell subsets

“…This suggestion is in line with a recent study showing that HIV-1 TAT protein specifically down-regulates cell surface expression of IL-7Ra on CD8 + T cells in a dose-and time-dependent manner [6]. Our results also confirm and extend findings from previous reports that IL-7 plays an important role in regulating lymphopoiesis [3][4][5]. We found that IL-7 levels were correlated negatively with CD4 + and CD8 + T cell subsets expressing IL-7Ra, and that these associations were stronger with CD4 + memory T cell subsets.…”

“…Other factors that influence disease progression have also been identified. We have reported previously that interleukin (IL)-7, a T cell regulatory cytokine, is a new independent predictor of disease progression and virological response to ART in HIV-1-infected adults [3]. We also reported recently that certain chemokines and growth factors known to be involved in HIV-1 pathogenesis, such as IL-15, regulated upon activation normal T cell expressed and secreted and transforming growth factor-b and that share some biological properties with IL-7, do not influence its predictive value [4].…”

Influence of RANTES, SDF‐1 and TGF‐β levels on the value of interleukin‐7 as a predictor of virological response in HIV‐1‐infected patients receiving double boosted protease inhibitor‐based therapy

“…The cytokine interleukin‐7 (IL‐7) has recently received special consideration because of its pivotal role in CD4 T‐cell homeostasis. We, and others, have reported that patients with low CD4 T‐cell counts show elevated levels of circulating IL‐7 and that these levels are inversely correlated with the number of CD4 T cells [5–7]. Moreover, we have shown that IL‐7 levels represent a new, independent predictor of virological response [5].…”

“…Plasma samples were stored at −80°C. Levels of IL‐7, RANTES, SDF‐1 and TGF‐β were measured by quantitative sandwich enzyme‐linked immunosorbent assay (R&D Systems, Minneapolis, MN) as previously reported [5]. All samples were thawed at room temperature, kept on ice and assayed in duplicate.…”

Skin-derived interleukin-7 contributes to the proliferation of lymphocytes in cutaneous T-cell lymphoma

“…IL-7 increases the survival of T cells in part by increasing the expression of antiapoptotic factor Bcl-2. 23 Interestingly, elevated levels of plasma IL-7 have been found in conditions of T-cell depletion, including after chemotherapy and HIV infection, [24][25][26] and IL-7 levels are inversely correlated with CD4 levels. 24,25 These studies support the notion that increased production of IL-7 may be a homeostatic mechanism for regulating T-cell proliferation and possibly thymic output.…”