7th Conference

LB1 A Potential Role for IL-7 in T-Cell Homeostasis in HIV Infected Patients.

T. J. FRY*¹, E. CONNICK², A. LANDAY³, M. M. LEDERMAN⁴, L. V. WOOD⁵, R. YARCHOAN⁵, and C. L. MACKALL¹. ¹POB, NCI, NIH, Bethesda, MD; ²Univ. of Colorado Hlth. Sci. Ctr. and VA Med. Ctr., Denver, CO; ³Rush Med. Coll., Chicago, IL; ⁴Case Western Reserve Univ. Sch. of Med. and Univ. Hosp. of Cleveland, OH; and ⁵HAMB, NCI, NIH, Bethesda, MD.

Background: Little is known about regulation of lymphocyte homeostasis. Given the profound, prolonged depletion of the lymphocyte compartment that occurs in HIV infection, identification of endogenous factors that contribute to T cell homeostasis may have important clinical implications. Interleukin-7 is required for thymopoiesis in the mouse, in part due to inhibition of apoptosis. In mature cells, IL-7 exerts a costimulatory effect, and we have observed enhanced thymic-independent, antigen-driven peripheral expansion of mature T cells by exogenous IL-7 during T-cell reconstitution. Therefore, IL-7 modulates multiple pathways of T-cell regeneration. Based upon these observations, we hypothesized that endogenous IL-7 could contribute to T-cell homeostasis.

Methods: In order to ascertain whether relationships between IL-7 levels and T-cell counts exist in patients with HIV infection, we studied 42 children enrolled on a combination protease inhibitor-based antiretroviral trial, 31 adults with moderate T-cell depletion enrolled on ACTG 315/375, and 20 adults with severe T-cell depletion treated on protocols at the NCI. IL-7 levels were measured in frozen serum or heparinized plasma using a colorimetric high-sensitivity ELISA.

Results: IL-7 levels were significantly higher in HIV-infected patients (range 1.7-57.2 pg/ml, mean 13.9 pg/ml) than normal values (range 0.27-8 pg/ml, mean 2.2 pg/ml). At baseline, there was a strong inverse correlation between IL-7 levels and absolute CD4 count (-0.77, p<0.0001 for children and -0.68, p<0.0001 for adults). An inverse correlation at baseline was also observed between IL-7 levels and CD4+CD45RA+ T cells in children (-0.70, p<0.0005) and between IL-7 levels and CD4+CD45RA+CD62L+ T cells in adults (-0.31, p<0.007). A subset of the pediatric group was followed longitudinally for 96 weeks after initiation of antiretroviral therapy. Patients with a good immunologic response to therapy showed temporally associated decreases in serum IL-7 levels.

Conclusion: These results are consistent with a model of IL-7 as a regulator of T-cell homeostasis, with increased production in response to CD4 T-cell deficiency in HIV infection. Furthermore, chronically high levels of IL-7 could contribute to the generalized state of T-cell activation observed in patients with T-cell depletion. Additional studies of the role of IL-7 in patients with HIV infection are warranted.

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