IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection

Abstract

Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-controlled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 microg/kg and a maximum tolerated dose of 30 microg/kg. Injection site reactions and transient elevations of liver function tests were the most notable side effects. Transient increases in plasma HIV-RNA levels were observed in 6 of 11 IL-7-treated patients. Recombinant hIL-7 induced CD4 and CD8 T cells to enter cell cycle; cell-cycle entry was also confirmed in antigen-specific CD8 T cells. Administration of rhIL-7 led to transient down-regulation of the IL-7 receptor alpha chain (CD127) in both CD4(+) and CD8(+) T cells. Single-dose rhIL-7 increased the numbers of circulating CD4(+) and CD8(+) T cells, predominantly of central memory phenotype. The frequency of CD4(+) T cells with a regulatory T-cell phenotype (CD25(high) CD127(low)) did not change after rhIL-7 administration. Thus, rhIL-7 has a biologic and toxicity profile suggesting a potential for therapeutic trials in HIV infection and other settings of lymphopenia. This clinical trial has been registered at http://www.clinicaltrials.gov under NCT0099671.

Trial registration: ClinicalTrials.gov NCT00099671 NCT00099671.

Figure 1

Pharmacokinetic data. (A) Plasma IL-7 levels by stratum and dose after rhIL-7 administration are shown. (B) The median AUC is plotted, demonstrating a nonlinear pharmacokinetic profile with small increases of the dose leading to large increases in AUC.

Figure 2

Changes in T-cell counts after rhIL-7 administration. (A) CD4⁺ and CD8⁺ T-cell counts decreased significantly on days 1 and 2 and increased significantly on day 14 after the rhIL-7 dose. ● represents placebo participants () and ▲ represents rhIL-7 participants (). (B) CD4⁺ and CD8⁺ T-cell changes from baseline according to rhIL-7 dose group. ● represents placebo participants () and rhIL-7 participants are represented by ▲ (3 μg/kg), ■ (10 μg/kg), ♦ (30 μg/kg), and X (60 μg/kg). (C) Central memory CD4⁺ and CD8⁺ T cells decreased significantly on day 1 and increased significantly on day 14 and day 28 (CD8⁺ T cells) after a single rhIL-7 administration. ● represents placebo participants () and ▲ represents rhIL-7 participants ().

Figure 3

Changes in CD127 expression on T cells after rhIL-7 administration. CD127-expressing CD4⁺ and CD8⁺ T cells decreased after rhIL-7 administration and re-emerged by day 4 among CD4⁺ T cells or day 14 among CD8⁺ T cells. P values represent comparisons between rhIL-7 and placebo recipients by Wilcoxon rank sum test. ● represents placebo participants () and ▲ represents rhIL-7 participants ().

Figure 4

Cycling of CD4⁺ and CD8⁺ T cells in response to rhIL-7. (A) Increased CD4⁺ and CD8⁺ T-cell cycling was seen on days 1 and 4, returning to baseline by day 14. (B) The degree of T-cell proliferation was higher at higher dosing levels. ● represents placebo participants () and ▲ represents rhIL-7 participants (). (C) Absolute counts of Ki67⁺ T cells during study participation by rhIL-7 dose. ● represents placebo participants () and rhIL-7 participants are represented by ▲ (3 μg/kg), ■ (10 μg/kg), ♦ (30 μg/kg), and X (60 μg/kg). P values represent comparisons between rhIL-7 and placebo recipients by Wilcoxon rank sum test.

Figure 5

Emergence of activated CD4⁺ and CD8⁺ T cells after rhIL-7 administration. Activated CD4⁺ and CD8⁺ T cells (HLA-DR⁺CD38⁺) increased on days 1 and 4 after rhIL-7 administration but remained unchanged in placebo recipients. ● represents placebo participants () and ▲ represets rhIL-7 participants ().

Figure 6

Characterization of Ag-specific CD8⁺ T cells during study participation. Phenotypic analysis of Ag-specific CD8⁺ T cells at baseline, day 4, and day 28. Significant increases in Ki67 expression were observed on day 4, returning to baseline on day 28. PD-1, CD127, and CD45RO/CD27 expression did not change significantly after rhIL-7 administration.

Figure 7

Emergence of immature/transitional B cells after rhIL-7 administration. (A) Example of contour plot demonstrating the emergence of CD27⁻CD10⁺CD21^low/high (immature/transitional) B cells at day 28. (B) Summary data from placebo and rhIL-7 recipients confirmed a statistically significant increase of the subset of immature/transitional B cells on day 28. PBMCs were gated on CD19⁺ cells and mature CD27⁺CD10⁺ B cells were excluded.