CD30, a member of the tumor necrosis factor (TNF) receptor family, is expressed constitutively on the surface of the human T cell line ACH-2, which is chronically infected with human immunodeficiency virus type-1 (HIV)-1. We demonstrate that cross-linking CD30 with an anti-CD30-specific monoclonal antibody, which mimics the described biological activities of the CD30 ligand (CD30L), results in HIV expression. CD30 cross-linking does not alter proliferation of ACH-2 cells and the induction of HIV expression is not mediated by endogenous TNF alpha/beta. Furthermore, cross-linking of CD30 leads to NF-kappa B activation and enhanced HIV transcription. Thus, CD30-CD30L interactions mediate the induction of HIV expression by a kappa B-dependent pathway that is independent of TNF. This mechanism may be important in the activation of HIV expression from latently infected CD4+ T cells, especially in lymphoid organs where cell to cell contact is conducive to receptor-ligand interactions.