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. 2017 Dec 19;12(12):e0188427.
doi: 10.1371/journal.pone.0188427. eCollection 2017.

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

Amanda K Steele  1   2 , Lorna Carrasco-Medina  3 , Donald L Sodora  1 , Angela M Crawley  4   5   6
Affiliations

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

Amanda K Steele et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Study design for the SIV infection, antiretroviral treatment and IL-7 therapy administration of Rhesus macaques.
Animals were infected with SIV at day 0, and antiretroviral (ART) was initiated 105 days post-infection (d.p.i), with a dose reduction 128 d.p.i. Animals who were administered rsIL-7-gly received 3 clusters of rsIL-7gly administered s.c. weekly for 3 weeks followed by 2 weeks between each cluster. All animals were administered BrDu daily for 4 days, starting 149 d.p.i. Each vertical line corresponds to date on which a collected plasma sample was utilized for the quantification of sCD127 in this study.
Fig 2
Fig 2. Plasma sCD127 concentrations are unaffected by SIV infection or antiretroviral therapy in Rhesus macaques.
The concentration of sCD127 in plasma samples of Rhesus macaques prior to SIV infection, after infection, following ART initiation (>105 d.p.i.) was determined using a CD127 microbead immunoassay. The minimum detection limit of the immunoassay is 5 ng/ml. (A) Plasma concentrations of sCD127 did not change following SIV infection or after ART (paired Student’s t-test, n = 4) in the control group. (B) The concentration of plasma sCD127 (mean, +/- SD) is shown relative to viral loads for each animal in the control group over time (0–380 d.p.i.). Plasma samples for RM23892 (day -7 until day 105 post-infection) could not be located for the quantification of sCD127 in this retrospective study.
Fig 3
Fig 3. Plasma sCD127 concentrations increased and persisted after IL-7 administration to ART-treated SIV-infected Rhesus macaques.
The concentration of sCD127 in plasma samples of Rhesus macaques prior to SIV infection, after infection, following ART initiation (>105 d.p.i.) and after each administration of IL-7 (started at 142 d.p.i.) was quantified by a CD127 microbead immunoassay (min. detection limit: 5 ng/ml). (A) Plasma sCD127 concentrations transiently increased in all SIV-infected, ART-treated animals that were administered rsIL-7-gly (n = 5). In some cases, these increases persisted for 3–5 weeks. (B) The concentration of plasma sCD127 (mean, +/- SD) is shown relative to viral loads for each animal in the IL-7-treated group over time (0–380 d.p.i.). (C-G) Changes in sCD127 concentrations also varied by IL-7 cluster, depending on the individual. In the first cluster of IL-7 administration, 3 of 5 animals (C, D and E) demonstrated a sharp increase in plasma sCD127 concentrations before the next cluster. The second cluster of IL-7 treatment increased sCD127 release in 2 animals (E and G). Plasma sCD127 concentrations increased in the third cluster in 3 of 5 animals (D, E and G). Transient increases in plasma sCD127 concentrations persisted for as long as 3–5 weeks following the last administration of IL-7 in a given cluster. Lastly, the magnitude and frequency of observed increases in sCD127 concentrations was most pronounced in animals that either (C) failed to suppress the virus with ART or (D, F and G) lost virological control, compared to (C) the virologically suppressed animal. The clustered administration of IL-7 is indicated on the x-axis by groups of three arrows labeled as clusters #1–3.
Fig 4
Fig 4. Increased plasma sCD127 concentrations correlated with IL-7-induced increases in CD8+ T-cells in SIV-infected Rhesus macaques.
(A-D) Representative graphs of IL-7-treated animals whose concentration of plasma sCD127 increased with changes in absolute CD8+ T-cell numbers in at least one IL-7 cluster during the cytokine treatment time period. (E) In the animal that maintained viral control, plasma sCD127 concentrations did not appear to associate with changes CD8+ T-cell numbers. Total number of IL-7-treated animals in which data of absolute T-cells was available: n = 5. The clustered administration of IL-7 is indicated on the x-axis by groups of three arrows.
Fig 5
Fig 5. Increased plasma sCD127 concentrations correlated with IL-7-induced increases in CD8+ T-cell subsets in SIV-infected Rhesus macaques.
All CD8+ T-cell subsets with statistically significant correlations with sCD127 are graphed here. Increasing concentrations of plasma sCD127 following IL-7 administration were positively correlated with increases in (A) total, (B) naïve TN, (C) transitional effector memory TTrM and (D) central memory TCM CD8+ T-cell subsets in SIV-infected, ART-treated Rhesus macaques (Spearman correlation analysis, r- and p-values are indicated on graphs).
Fig 6
Fig 6. Plasma sCD127 concentrations associated with IL-7-induced activation of CD4+ T-cells in SIV-infected, ART-treated Rhesus macaques.
These effects were observed frequently among animals in this study, yet varied by IL-7 treatment cluster (depicted by arrows). (A-D) Increases of sCD127 paralleled the changes in Ki67+CD4+ TN and TCM cell numbers in 3 out of 4 animals evaluated, specifically (A) RM22657, (B) RM23686 and (C) RM23750.
Fig 7
Fig 7. Plasma sCD127 concentrations associated with IL-7-induced activation of CD4+ T-cells in SIV-infected, ART-treated Rhesus macaques.
The concentration of plasma sCD127 increased as the number of activated CD8+ TEM cells increased in all 4 animals treated with IL-7. Total number of IL-7-treated animals in which T-cell activation data (Ki67 assay) was available: n = 4 (data for the 5th animal in this group is not available for this parameter of the study). The clustered administration of IL-7 is indicated on the x-axis by groups of three arrows.
Fig 8
Fig 8. IL-7 therapy-mediated effects on T-cell survival is associated with increases in plasma sCD127 concentrations.
The concentration of plasma sCD127 was compared to T-cell survival, as assessed by BrDU uptake. Starting at 142 d.p.i, animals received 4 daily injections of BrDU. The number of circulating BrDU+ CD4+ and CD8+ T-cells was determined every 7 days until 373 d.p.i. (A) The survival profiles of T-cells in each of the SIV-infected, ART-treated Rhesus macaques in the control group are shown.
Fig 9
Fig 9. IL-7 therapy-mediated effects on T-cell survival is associated with increases in plasma sCD127 concentrations.
T-cell survival graphs for all animals in the IL-7 treatment group. In all plots, an arbitrary, yet common crossing point of 5 BrDU+ cells/μl of blood is indicated by a dotted line. The clustered administration of IL-7 is indicated on the x-axis by groups of three arrows and the first day of the BrDU injections is also indicated.
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