Serum IgE levels are increased in adults and children with HIV-1 infection and could be a marker of poor prognosis. Allergic reactions and adverse reactions to drugs are also increased in HIV-1–infected individuals. An imbalance between a TH1-like and a TH2-like cytokine profile has been documented in HIV-1 infection. We have found that HIV-1 gp120 from different clades is a potent stimulus for histamine and cytokine (IL-4 and IL-13) release from basophils. Gp120 acts as a viral superantigen, interacting with the VH3 region of IgE to induce mediator release from human FcϵRI+ cells. Human basophils and mast cells express the chemokine receptor CCR3, which binds the chemokines eotaxin and RANTES. By interacting with the CCR3 receptor on FcϵRI+ cells, HIV-1 Tat protein is a potent chemoattractant for human basophils and lung mast cells. Tat protein also induced IL-4 and IL-13 release from basophils. Preincubation of basophils with Tat protein upregulated the surface expression of the CCR3 receptor. Extracellular Tat can influence the directional migration of human FcϵRI+ cells, the expression of chemokine receptor CCR3, and the release of TH2 cytokines. Because Tat protein is actively released by HIV-1–infected cells, our results indicate a novel mechanism by which FcϵRI+ cells are rendered more susceptible to infection with CCR3-tropic HIV-1 isolates; that is, two HIV-1 proteins, gp120 and Tat, trigger the release of cytokines critical for TH2 polarization from FcϵRI+ cells, and Tat upregulates β-chemokine receptor CCR3 on these cells. (J Allergy Clin Immunol 2001;107:22-30.)