Expression of the interleukin-7 receptor alpha-chain is down regulated on CD4 T-cells by the HIV-1 Tat protien

Abstract

HIV infection elicits defects in CD4 T-cell homeostasis in both a quantitative and qualitative manner. Interleukin-7 (IL-7) is essential to T-cell homeostasis and several groups have shown reduced levels of the IL-7 receptor alpha-chain (CD127) on both CD4 and CD8 T-cells in viremic HIV+ patients. Our lab has demonstrated that soluble HIV Tat protein specifically down regulates cell surface expression of CD127 on human CD8 T-cells. Once taken up by CD8 T-cells, Tat enters the cytoplasm and interacts directly with the cytosolic tail of CD 127 inducing receptor capping, endocytosis and degradation. The purpose of this study is to determine if, similar to CD8 T-cells, HIV Tat down regulates surface CD127 expression on CD4 T-cells and if this down regulation affects IL-7 signaling. To investigate this, primary CD4 T-cells isolated from healthy HIV-negative volunteers were incubated in medium alone or with Tat protein (10 ug/ml) for up to 72 hours and then analyzed by flow cytometry. As anticipated, soluble HIV Tat protein induces a significant decrease in surface CD127 expression on CD4 T-cells relative to cells cultured in medium alone. The effect was dose and time dependent, reversible, and could be blocked with anti-Tat antibodies or heparin. Tat down regulated CD127 equally on naive and memory cells and did not require new protein synthesis to have its effect. Tat's down regulation of CD127 was not associated with cell activation as there was no change in overall cell phenotype including expression of CD25 and CD56. Further, expression of CD132, the common gamma-chain which associates with CD127 to form the IL-7 receptor, was also unaffected by Tat. Notably, down regulation of CD127 by Tat resulted in lower induction of the anti-apoptotic protein Bd-2 following stimulation with IL-7. In view of the important role IL-7 plays in CD4 T-cell proliferation, homeostasis and survival, this down regulation of CD127 by Tat may well play a role in HIV-induced immune dysregulation and CD4 T-cell decline. Understanding this effect could lead to new therapeutic approaches to reverse the CD4 T-cell loss evident during HIV infection.