Vpx is required for dissemination and pathogenesis of SIVSM PBj: Evidence of macrophage-dependent viral amplification

The viral accessory protein Vpx is required for productive in vitro infecti on of macrophages by simian immunodeficiency virus from sooty mangabey monk eys (SIVSM). To evaluate the roles of Vpx and macrophage infection in vivo, we inoculated pigtailed macaques intravenously or intrarectally with the m olecularly cloned, macrophage tropic, acutely pathogenic virus SIVSM PBj 6. 6, or accessory gene deletion mutants (Delta Vpr or Delta Vpx) of this viru s. Both wild-type and SIVSM PBj Delta Vpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplific ation of infection and dissemination was observed for wild-type virus, but not for SIVSM PBj Delta Vpx, which also showed considerable impairment of t he overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIVSM Pbj Delta Vpx intravenously ol intrarectally, the Delta Vpx mutant was at a strong competitive disadva ntage. Vpx-dependent viral amplification at local sites of initial infectio n, perhaps through a macrophage-dependent mechanism, may be a prerequisite for efficient dissemination of infection and pathogenic consequences after exposure through either mucosal or intravenous routes.