IL-7 Induces Immunological Improvement in SIV-Infected Rhesus Macaques under Antiviral Therapy

Abstract

Despite efficient antiretroviral therapy (ART), CD4+ T cell counts often remain low in HIV-1-infected patients. This has led to IL-7, a crucial cytokine involved in both thymopoiesis and peripheral T cell homeostasis, being suggested as an additional therapeutic strategy. We investigated whether recombinant simian IL-7-treatment enhanced the T cell renewal initiated by ART in rhesus macaques chronically infected with SIVmac251. Six macaques in the early chronic phase of SIV infection received antiretroviral treatment. Four macaques also received a 3-wk course of IL-7 injections. Viral load was unaffected by IL-7 treatment. IL-7 treatment increased the number of circulating CD4+ and CD8+ memory T cells expressing activation (HLA-DR+, CD25+) and proliferation (Ki-67+) markers. It also increased naive (CD45RAbrightCD62L+) T cell counts by peripheral proliferation and enhanced de novo thymic production. The studied parameters returned to pretreatment values by day 29 after the initiation of treatment, concomitantly to the appearance of anti-IL-7 neutralizing Abs, supporting the need for a nonimmunogenic molecule for human treatment. Thus, IL-7, which increases T cell memory and de novo renewal of naive T cells may have additional benefits in HIV-infected patients receiving ART.

Interleukin 7 reduces the levels of spontaneous apoptosis in CD4+and CD8+T cells from HIV-1-infected individuals

“…Studies of IL-7 administration to uninfected and SIV-infected macaques have demonstrated a proliferative effect on CD4 ϩ and CD8 ϩ T cells expressing both memory and naïve phenotypes (27,28,38). Analogous results were obtained more recently in human cancer patients (39), as well as in HIV-1-infected individuals (M. Lederman, personal communication).…”

“…At doses that promote T cell proliferation, IL-7 has been reported to induce the transcription of latent HIV-1 in resting peripheral blood CD4 ϩ T cells derived from infected patients on antiretroviral therapy cultured for several weeks ex vivo (26). However, in vivo administration of IL-7 to SIVinfected macaques did not cause a detectable increase in viral load both in lymph nodes and in peripheral blood, despite a widespread induction of T cell proliferation (27,28).…”

Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques

“…Both IL-7 and IL-15 are cytokines produced by stromal cells that directly affect the homeostatic proliferation of memory T cells and regulate effector function (63,64). Prior studies on naive or SIV-infected macaques treated with rIL-7 protein have demonstrated that this cytokine alters T cell homeostasis (27,28,65) without altering SIV replication (66). The use of rIL-15 has been pioneered in naive macaques alone or together with Ags (26) and has been demonstrated to increase the frequency of long-lived CD4 ϩ and CD8 ϩ T cells.…”

“…In uninfected macaques immunized with tetanus toxoid or a live flu vaccine, rIL-15 increased long-term memory responses (26). In contrast, the administration of rIL-7 to healthy or SIV-infected macaques increased the proliferation of all T cell subsets and enhanced de novo thymic production (27)(28)(29).…”

Fighting Fire with Fire in Cancer

“…Although IL-7 treatment had already shown significant therapeutic promise [20][21][22], and had been successfully used in several nonhuman primate SIV infection models [23][24][25], the efficacy of IL-7 in promoting viral clearance had not been fully explored [19]. We administered IL-7 to mice infected with LCMV clone 13, which establishes a chronic infection and generates massive viral antigen levels [26].…”