Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions

Nef of primate lentiviruses is critical for high levels of viremia and the progression to AIDS. Nef associates with and activates a serine/threonine k inase (Nef-associated kinase [NAK]) via the small GTPases Rac1 and Cdc42. W e identified the protooncogene and guanine nucleotide exchange factor Vav a s the specific binding partner of Nef proteins from HIV-1 and SIV. The inte raction between Nef and Vav led to increased activity of Vav and its downst ream effecters. Both cytoskeletal changes and the activation of c-Jun N-ter minal kinase (JNK) were observed. Furthermore, a dominant-negative Vav prot ein inhibited NAK activation and viral replication. Thus, the interaction b etween Nef and Vav initiates a signaling cascade that changes structural an d physiological parameters in the infected cell.