Background:  Interleukin-7 (IL-7) is a central regulator of T-cell homeostasis and acts via the IL-7 receptor (IL-7R), which consists of a specific a-chain (CD127) dimerized to the common g-chain (CD132). IL-7 is elevated in HIV-associated lymphopenia, and an association between CD127 down-regulation and loss of cytotoxic lymphocyte function has been reported. The effect of elevated plasma IL-7 on IL-7R component expression, disease progression, and immune reconstitution remain unclear.

Methods:  Healthy volunteers and patients with primary, and chronic HIV infection (PHI, CHI) were studied prior to and following 40 to 48 weeks of ART. Long-term non-progressors (LTNP-c) were matched with LTNP who went on to lose viral control (LTNP-loc) for length of infection and studied at cohort entry and 12 to 24 months after LTNP-loc lost viral control. Plasma IL-7 levels were measured by commercial ELISA. Expression of CD127 and CD132 on CD45RO⁺ and CD45RO^­ CD4 and CD8 T-cell surface were measured by flow-cytometry. Plasma IL-7 levels were compared with those of healthy volunteers and correlated with clinical data and IL-7R expression using non-parametric analysis.

Results:  IL-7 levels were elevated in PHI (median 2.35 pg/mL) and CHI (3.07pg/mL) at baseline, compared to healthy volunteers (1.25 pg/mL; p <0.01 and p <001). ART resulted in normalized IL-7 levels in PHI (1.46 pg/mL; p = 0.67) but not CHI (2.05 pg/mL; p <0.01). Plasma IL-7 levels positively correlated with CD4 T-cell immune reconstitution in PHI (r = 0.47; p <0.05). HIV infection resulted in significant decreases in the CD127⁺132^­ and increases in the CD127^­132⁺ subset of CD4 and CD8 T cells, in both naïve and memory T cells. Plasma IL-7 levels positively correlated with the size of the CD4⁺127^­132⁺ pool (r = 0.42; p <0.05) and negatively correlated with the size of the CD4⁺127⁺132^­ pool (r = ­0.44; p <0.01). Absolute pre-therapy CD4 count inversely correlated to CD4⁺127^­132⁺ T-cell percentage (r = ­0.64; p <0.0001) and positively correlated to size of CD4⁺127⁺132^­ pool (r = 0.43; p <0.05). Changes in CD4 T-cell expression of IL-7R components were evident in LTNP-loc at cohort entry and preceded increases in plasma IL-7.

Conclusions: Dysregulation of the IL-7/IL-7R system occurs early in HIV infection with marked reductions in the proportions of CD4 T-cells expressing CD127. The extent of this down regulation is associated with loss of viral control in LTNP. The mechanism of this depletion is the subject of ongoing investigation.