NEF PROTEINS OF DISTINCT HIV-1 OR HIV-2 ISOLATES DIFFER IN THEIR BINDING-PROPERTIES FOR HCK - ISOLATION OF A NOVEL NEF BINDING-FACTOR WITH CHARACTERISTICS OF AN ADAPTER PROTEIN

The Nef gene of the human and simian immunodeficiency viruses HIV and SIV has been implicated in pathogenicity; however, the mechanism by wh ich Nef induces disease is still unknown. An impact on signal transduc tion in cells has been suggested by the interaction of Nef from an HIV -I strain and tyrosine kinases like HCK and LCK as well as serine/thre onine kinases. We have confirmed the binding of HCK to HIV-1 subtype B Nef and demonstrated an equally strong interaction with a subtype E N ef protein but weaker binding to Nef of HIV-2 subtype A (HIV-2(D194)). No binding, however, was observed to HIV-2 subtype B Nef (HIV-2(D205) ). Instead, this protein bound to a novel cellular protein, Nefin1, wi th characteristics of an adaptor protein and strong expression in all human hematopoietic tissues. Nefin1 binds through an amino-terminal do main, which is related to SH3 domains. For interaction of Nef with Nef in1, the PxxP motif and the three-dimensional conformation of the mole cule appear necessary. In conclusion, this study demonstrates that Nef proteins of divergent strains of HIV-1 and HIV-2 may use different el ements of signal transduction pathways for the induction of pathogenic ity in vivo. (C) 1998 Academic Press.