Cutting edge: JAK3 activation and rescue of T cells from HIV gp120- induced unresponsiveness

In early HIV disease, immunodeficiency is characterized by the inability of CD4⁺ T cells to produce a critical cytokine, IL-2, and to express the receptor for IL-2 (IL-2R) in response to antigenic or mitogenic stimulation. The shared common γ-chain (γ(c)) of IL-2R and its associated Janus kinase, JAK3, are indispensable for normal T cell function. Here, we show that the inhibition of IL-2R expression and proliferation induced by ligation of CD4 by HIV enveloped glycoprotein, gp120, is correlated with inhibition of expression and activation of JAK3. Stimulation through the γ(c)-related cytokine receptors restores JAK3 expression and activation and rescues CD4- mediated T cell unresponsiveness. Collectively, these data argue that inhibition of JAK3 expression and activation may, in part, explain the T cell dysfunction seen in early HIV disease. In addition, rescue from gp120- mediated T cell unresponsiveness by activation of JAK3 suggests a novel therapeutic approach for enhancing immune function in HIV disease.