Increased soluble IL-7 receptor concentrations associate with improved IL-7 therapy outcomes in SIV-infected ART-treated Rhesus macaques

Abstract

The use of interleukin-7 (IL-7) as an immunorestorative therapeutic has proven effective in HIV infection, cancer and bone marrow transplantation. Mediating its activity through membrane-bound IL-7 receptor α (mCD127), IL-7 therapy increases T-cell numbers and survival. A soluble form, sCD127, is found in plasma, and we have previously identified increased plasma sCD127 concentrations in HIV infection. Furthermore, patients with high sCD127 exhibited the best viral control, implicating a role for IL-7 or sCD127 directly in improved virologic/immunologic outcomes. The role of the cytokine IL-7 in elevating sCD127 levels was addressed here through assessment of retrospective samples obtained from SIV-infected antiretroviral (ART)-treated Rhesus macaques. IL-7 was administered in clustered weekly doses, allowing for an assessment prior, during and following IL-7 administration. The levels of sCD127 remained relatively unchanged during both early SIV infection and following initiation of ART. However, treatment with IL-7 increased sCD127 concentrations in most animals, transiently or persistently, paralleling increased T-cell numbers, correlating significantly with CD8+ T-cell levels. In addition, proliferating CD4+ or CD8+ T-cells (measured by Ki67) increased in association with elevated sCD127 concentrations. Finally, a high concentration of sCD127 in IL7-treated animals was associated with increased retention of T-cells (measured by BrDU). In addition, a lack, or loss of viral control was associated with more pronounced and frequent elevations in plasma sCD127 concentrations with IL-7 therapy. In summary, plasma sCD127 levels in SIV-infected ART-treated macaques was associated with therapeutic IL-7 administration, with higher sCD127 levels in macaques demonstrating the best T-cell responses. This study furthers our knowledge regarding the interrelationship between increased IL-7 levels and elevated sCD127 levels that may have implications for future IL-7 immunotherapeutic approaches in HIV-infected patients.

Increased Regulatory T-Cell Activity and Enhanced T-Cell Homeostatic Signaling in Slow Progressing HIV-infected Children

“…However, recent data demonstrate that the bio-activity of IL-7 is directly enhanced by the presence of soluble CD127 (sCD127) (57). Indeed, the positive benefit of IL-7 therapy in SIV infected rhesus macaques was dependent on high levels of sCD127 (58). We therefore measured plasma levels of IL-7 and sCD127 in HIV-infected children.…”

“…However, lower levels of sCD127 have been observed by others in HIV-infected patients compared to healthy controls (89). Moreover, higher levels of sCD127 in plasma were associated with improved immune reconstitution in SIV infected rhesus macaques treated with recombinant IL-7 (58). The potentiating effect of sCD127 on IL-7 signaling is supported by mechanistic studies showing it enhances the bioactivity of IL-7 when the cytokine is limiting, as it is presumed to be the situation in-vivo (57, 59).…”

IL7RA single nucleotide polymorphisms are associated with the size and function of the MAIT cell population in treated HIV-1 infection

“…However, the effects of sIL-7Ra in shaping IL-7 bioavailability are complex. Several reports demonstrated that sIL-7Ra serves as a reservoir of IL-7 and hence increases its half-life due to relatively low affinity (53,60). Lundström et al provided a model for sIL-7Ra-mediated IL-7 regulation, proposing that sIL-7Ra/rhIL-7 with a very high molar ratio (>5000) may increase the bioactivity of IL-7 by stabilizing its reservoir (53).…”

“…However, the effects of sIL-7Rα in shaping IL-7 bioavailability are complex. Several reports demonstrated that sIL-7Rα serves as a reservoir of IL-7 and hence increases its half-life due to relatively low affinity ( 53 , 60 ). Lundström et al.…”

Chimeric antigen receptor T-cell approaches to HIV cure

“…Rational selection of cytokines during T-cell culture, e.g. favoring IL7 and IL15 over IL2, may also aid in the generation of a more robust T-cell product [58,59]. T-cell exhaustion could also be targeted; similar to cancer patients, HIV infected individuals' T-cells express higher levels of PD1 [60,61], Tim3 [62], and other exhaustion markers.…”