Intermittent Interleukin-2 Therapy Induces the Expansion of Naïve and Central Memory CD4 T Cells and Has No Impact on HIV-specific T-cell Responses in ART-naïve HIV-infected Patients: Immunological Substudy of the ANRS 119 Interstart Trial
A Venet1, Marie-Lise Gougeon*2, S Hamonic3, C Lacabaratz1, D Séréni4, M Bentata5, I Fournier3, J P Aboulker3, J M Molina4, Y Lévy6, and ANRS 119 Interstart group
1INSERM U802, Univ Paris XI, Kremlin Bicetre, France; 2Pasteur Inst, Paris, France; 3INSERM SC10, Villejuif, France; 4Hosp St Louis, Paris, France; 5Hosp Avicenne, Bobigny, France; and 6Henri Mondor Hosp, Creteil, France
Background: Interleukin-2 (IL-2) therapy leads to an
increase of naïve and central memory CD4 T cells in HIV-infected patients treated with ART. Effects of IL-2 on T-cell
homeostasis and functions in HAART naïve patients are less known. These
questions were addressed in a subgroup of patients enrolled in the ANRS 119
study aimed to evaluate IL-2 as a strategy to delay ART.
Methods: We randomized 130 ART-naive patients, with
300 to 500 CD4/mm3, to receive
either 3 subcutaneous IL-2 cycles at weeks 0, 8, and 16 (4.5 MIU, twice daily,
5 days) or no treatment. Phenotyping was performed on naive (CD45RA+CCR7+),
central memory (CD45RA–CCR7+), effector memory (CD45RA–CCR7–),
and effector (CD45RA+CCR7–) CD4 and CD8 T cells. HIV-1-specific
CD4 and CD8 T-cell responses were assessed by interferon-γ (IFN-γ)
ELISpot assays using either Gag p24 protein or 18 pools of 192 HIV-derived
peptides (15-mers), respectively. Analyses were performed in 50 patients
(26 IL-2 and 24 control patients) at week 0 and week 24.
week 24, median changes (absolute number of cells/mm3) from baseline
were +19, +59, +20, and –9 for naive, central memory, effector memory and effector
CD4 T cells in IL-2-treated patients as compared with –29, –15, +20, and –13
for similar subsets in control patients (p
= 0.024 and 0.035 for naive and central memory subsets). No significant
changes in CD8 T-cell subsets were observed in the 2 groups, and IL-2 did not
induce any changes in perforin expression. At baseline, 68% and 70% (control
and IL-2 groups, respectively) had HIV-1 specific CD4 T-cell responses.
Magnitude of these responses among responders was: 328 (IQR 162 to 628)
(control group) and 304 (IQR 109 to 745) spot-forming cells (SFC)/106
peripheral blood mononuclear cells (PBMC) (IL-2 group). At week 24, the percentage
of responders decreased in the IL-2 group (43%, p = 0.058), as well as the magnitude of CD4 responses in the week-24
responders (119 SFC/106 PBMC, p
= 0.027), whereas no changes were noted in control group. The frequency of patients
with HIV-specific CD8 cell responses and the magnitude of their responses,
similar at week 0 in the 2 groups, remained unchanged at week 24.
in patients with controlled HIV replication, IL-2 led to a significant increase
of naive and central memory CD4 cells in ART-naive patients. Despite ongoing
HIV replication, IL-2 did not affect HIV-specific effector T-cell responses.
These data suggest that viral replication does not hamper IL-2 effects on
T-cell homeostasis, which was the hypothesis of the rationale of its use in the
ANRS 119 study.