It has been much debated as to whether CD4+ T-cell depletion and the pathogenesis of AIDS is the result of direct cytolytic effects of human immunodeficiency virus (HIV), T-cell apoptosis by nonspecific activation, dysregulation of cytokine production, or autoimmunity. In this context, Rolf Zinkernagel and Hans Hengartner discuss data from model infections with non-cytopathic viruses. They suggest that HIV may cause immunosuppression, not by direct cytolytic effects, but rather by a conventional virus-specific cytotoxic T-cell-mediated immunopathology.