HIV-1 infection in CD4(+) T cells initiates a viral cytopathic effect (CPE) that is dependent on the activation of intracellular protein tyrosine kinases (PTK). PTK in T cells are also activated during the course of TCR or CD4 receptor engagement and the manner of receptor engagement may generate signals leading either to cell proliferation, tolerance induction (anergy) or programmed cell death (PCD). We have identified PTK triggered during the interaction of cells stably expressing surface HIV envelope (gp 120/gp41; HIVenv) and CD4(+)T cells, which leads to extensive and rapid individual cell death. We have found that killing is accompanied by tyrosine phosphorylation and activation of the CD4-associated p56(ICK) kinase, and by activation of a second member of the scr family of PTK, p59(fyn) kinase, normally associated with T cell stimulation through the TCR. Interestingly, in contrast with normal T cell signaling, the zeta subunit of the TCR fails to become tyrosine-phosphorylated during signaling accompanying HIV-directed cell killing. Downstream activation of the ZAP-70 PTK also does not occur. Unlike T cell apoptosis triggered by soluble HIVenv glycoproteins, which requires co-stimulation of CD4 and the antigen-specific TCR, T cell killing by membrane-associated HIVenv does not require TCR co-stimulation, because aberrant signaling and cell death are triggered by CD4(+) but TCR- cell lines. These results are the first report where dual activation of the Lck and Fyn PTK does not result in normal downstream signaling through the ZAP PTK, We suggest by analogy to SCID resulting from ZAP-70 mutations, that the dissociation of upstream PTK activation from ZAP-70 signaling contributes to T cell depletion by HIV and to the development of AIDS.