Nef proteins of distinct HIV-1 or -2 isolates differ in their binding properties for HCK: Isolation of a novel Nef binding factor with characteristics of an adaptor protein

Abstract

The Nef gene of the human and simian immunodeficiency viruses HIV and SlY has been implicated in pathogenicity; however, the mechanism by which Nef induces disease is still unknown. An impact on signal transduction in cells has been suggested by the interaction of Nef from an HIV-1 strain and tyrosine kinases like HCK and LCK as well as serine/threonine kinases. We have confirmed the binding of HCK to HIV-1 subtype B Nef and demonstrated an equally strong interaction with a subtype E Nef 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, Nef in 1, with characteristics of an adaptor protein and strong expression in all human hematopoietic tissues. Nefin1 binds through an amino-terminal domain, which is related to SH3 domains. For interaction of Nef with Nefin1, the PxxP motif and the three-dimensional conformation of the molecule appear necessary. In conclusion, this study demonstrates that Nef proteins of divergent strains of HIV-1 and HIV-2 may use different elements of signal transduction pathways for the induction of pathogenicity in vivo.