Cover photograph (Copyright © 2000, American Society for Microbiology. All rights reserved.): Model for the cellular activation by Nef. Nef and Rac1/Cdc42 are targeted to cellular membranes by myristyl and geranyl moieties, respectively. Nef binds to Vav and induces its GEF activity, which then activates Rac1 and Cdc42. Nef also recruits Pak1/2 to this complex. Rac1-GTP and Cdc42-GTP then bind and activate Pak1/2. The activation of Pak1/2 triggers a series of downstream events, which include cytoskeletal rearrangements and the activation of Jnk, leading to optimal levels of viral replication. (See related article on page 2619-2627.)