MUTATION OF THE LCK-BINDING MOTIF OF TIP ENHANCES LYMPHOID-CELL ACTIVATION BY HERPESVIRUS SAIMIRI

The proline-rich SH3-binding (SH3B) motif of the tyrosine kinase-inter acting protein (Tip) of herpesvirus saimiri (HVS) is required for bind ing to the cellular Src family kinase Lck. We constructed a mutant for m of HF'S in which prolines in the SH3B motif of Tip were altered to a lanines. This mutant form of Tip was incapable of binding to Lck The m utant virus, HVS/Tip mSH3B, retained its ability to immortalize common marmoset lymphocytes in culture. In fact, common marmoset lymphocytes immortalized by the HVS/Tip mSH3B mutant displayed increased expressi on of HLA-DR lymphocyte activation marker, an altered pattern of tyros ine phosphorylation, increased expression of the tyrosine kinase Lyn, and a shift in electrophoretic mobility of Lck compared to cells immor talized by wild-type HVS. Experimental infection of common marmosets r esulted in fulminant lymphoma with both HVS/Tip mSH3B and wild-type HV S. However, HVS/Tip mSH3B produced greater infiltration of affected or gans by proliferating lymphoid cells compared to wild-type HVS. These results demonstrate that Tip binding to Lck is not necessary for trans formation and that abrogation of Tip binding to Lck alters the charact eristics of transformed cells and the severity of the pathologic lesio ns.