Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study

Y Lévy, I Sereti, G Tambussi, J P Routy, J D Lelièvre, J F Delfraissy, J M Molina, M Fischl, C Goujard, B Rodriguez, C Rouzioux, V Avettand-Fenoël, T Croughs, S Beq, M Morre, J F Poulin, R P Sekaly, R Thiebaut, M M Lederman, Y Lévy, I Sereti, G Tambussi, J P Routy, J D Lelièvre, J F Delfraissy, J M Molina, M Fischl, C Goujard, B Rodriguez, C Rouzioux, V Avettand-Fenoël, T Croughs, S Beq, M Morre, J F Poulin, R P Sekaly, R Thiebaut, M M Lederman

Abstract

Background: The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined.

Methods: We performed a randomized placebo-controlled dose escalation (10, 20 and 30 µg/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/µL and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored.

Results: Doses of rhIL-7 up to 20 µg/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/µL at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity.

Conclusions: Three weekly doses of rhIL-7 at 20 µg/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies.

Clinical trials registration: NCT0047732.

Figures

Figure 1.
Figure 1.
Changes in T-cell counts after recombinant human interleukin 7 (rhIL-7) administration. A, B, CD4 (A) and CD8 (B) T-cell counts (median, Quarter 1–Quarter 3) increased significantly at week 12 (day 77) after a rhIL-7 cycle (1 injection weekly for 3 weeks) (P < .002, representing changes from baseline for each dose group compared with placebo). The increase was dose-dependent for both CD4 and CD8 T cells and remained significant at week 52 (P < .005 and P < .01 for CD4 and CD8, respectively). C–F, Naive and central memory CD4 and CD8 T-cell subsets increased after rhIL-7 administration (P < .05 represents comparisons between the 20 and 30 µg/kg dose groups and placebo group by Wilcoxon rank sum test). G, Administration of rhIL-7 increased absolute counts of regulatory T cells (Tregs), but their frequency was significantly decreased. Abbreviations: CM, central memory; N, naive.
Figure 2.
Figure 2.
Cycling of CD4 and CD8 T-cell subsets in response to recombinant human interleukin 7 (rhIL-7). A, Flow cytometry was used to determine Ki-67 expression in T-cell subsets. Increased naive, central memory (CM), and effector memory T-cell cycling was seen on day 7 (pooled rhIL-7 groups compared with placebo, P < .001), returning to baseline by day 28 (median, Quarter 1–Quarter 3). The increase was not dose dependent and occurred in both CD4 and CD8 subsets. B, PD-1 expression decreased on both CD4 and CD8 T cells 28 days after 20 and 30 µg/kg rhIL-7 administration (P < .05 for each). The decrease persisted until day 77 (P < .05 ). C, CM subsets showed decreased expression of PD-1. Abbreviations: CM, central memory; EM, effector memory; N, naive.
Figure 3.
Figure 3.
Recombinant human interleukin 7 (rhIL-7) therapy increases numbers of naive and recent thymic emigrants (RTE) CD4 T cells and broadens the T-cell receptor (TCR) repertoire in a few subjects. Data shown are for subjects who received 3 doses of rhIL-7 at 20 or 30 µg/kg. A, Thymic activity was evaluated using the sj/β T-cell receptor excision circles (TREC) ratio. Treatment with rhIL-7 increased the number of naive and RTE cells in the peripheral blood on day 77 (P < .05, 20 and 30 µg/kg pooled data). The sj/β TREC ratio tended to increase (P = .06, pooled data for 20 and 30 µg/kg). B, The CD4 T-cell count at day 0 and CD4 nadir were associated with a change in the sj/β TREC ratio between days 0 and 77 (P = .01; Spearman's test). C, Subjects with lower CD4 T-cell counts experienced greater increases in thymopoiesis after rhIL-7 treatment. TCR repertoire diversity was assessed by quantifying all possible combinations between Vβ and Jβ segments. Shaded area represents range of diversity in historical controls. Diversity increased in all rhIL-7–treated subjects with diversity below the normal range but not significantly for the treated groups overall. D, Distribution of peaks for each Vβ-Jβ rearrangement for a placebo-treated and a rhIL-7–treated patient. Abbreviations: RTE, recent thymic emigrant; TREC, T-cell reception excision circle.

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