Abstract
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/µL 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.
Highlights
Human Immunodeficiency virus (HIV) infection is characterized by a profound depletion of CD4+ T cell numbers and function
We have developed a mathematical model to approximate the effect of IL-7 on CD4+ T cell homeostasis to fit the data from two phase I trials of IL-7 intervention in HIV-infected patients
IL-7 induced a sustained increase of all CD4+ T cell subsets Chronically HIV-1 infected patients with CD4+ T cell counts between 100 and 400 cells/mL and plasma HIV RNA,50 copies (c)/mL while on antiretroviral therapy were studied in three phase I/II trials
Summary
Human Immunodeficiency virus (HIV) infection is characterized by a profound depletion of CD4+ T cell numbers and function. Immune restoration with combination antiretroviral therapies (cART) has substantially improved patients’ outcomes. In HIV-infected patients, a strong inverse correlation has been observed between plasma IL-7 levels and CD4+ T cell numbers as well as with CD4+ T cell reconstitution after initiation of antiretroviral therapy [16,17,18,19]. Recent analyses of lymph node tissues have shown that collagen deposition may restrict T-cell access to IL-7, resulting in apoptosis and depletion of T cells [23]. This in turn leads to decreased production of lymphotoxin B, a trophic factor for reticuloendothelial cells, leading to their demise and loss of IL-7 producing cells. The IL-7 effect on CD4+ T-cell homeostasis is highly compromised in HIV infection [24]
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