Receptor-mediated activation was analyzed in T and B lymphocytes from normal mice and from mice infected with the MAIDS-inducing defective murine leukemia virus. Several weeks after viral infection, the proliferative responses of T and B cells to cross-linking of TCR and sIg respectively were significantly reduced despite the expression of normal surface levels of these receptors by most T and B cells. To analyze early signaling events in these cells, [Ca2+]i was measured in response to surface receptor cross-linking. The [Ca2+]i responses of both T and B cells from MAIDS-infected mice were decreased. B cell responses to sIg cross-linking were further analyzed by examining protein tyrosine phosphorylation induced by sIg cross-linking. It was found that after virus infection, there was a progressive loss of selected tyrosine phosphorylation events with conservation of other events. The response defect in B cells from MAIDS mice is thus reflected in selected alterations of tyrosine phosphorylation in response to sIg signaling.