title: Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification.
abstract: The viral accessory protein Vpx is required for productive in vitro infection of macrophages by simian immunodeficiency virus from sooty mangabey monkeys (SIV(SM)). To evaluate the roles of Vpx and macrophage infection in vivo, we inoculated pigtailed macaques intravenously or intrarectally with the molecularly cloned, macrophage tropic, acutely pathogenic virus SIV(SM) PBj 6.6, or accessory gene deletion mutants (deltaVpr or deltaVpx) of this virus. Both wild-type and SIV(SM) PBj deltaVpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplification of infection and dissemination was observed for wild-type virus, but not for SIV(SM) PBj deltaVpx, which also showed considerable impairment of the overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIV(SM) Pbj deltaVpx intravenously or intrarectally, the deltaVpx mutant was at a strong competitive disadvantage. Vpx-dependent viral amplification at local sites of initial infection, 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.
authors.affiliation: Laboratory of Molecular Microbiology, NIAID Twinbrook Facility, Rockville, Maryland 20852, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Hirsch
authors.forename: M E
authors.initials: ME
authors.lastname: Sharkey
authors.forename: C R
authors.initials: CR
authors.lastname: Brown
authors.forename: B
authors.initials: B
authors.lastname: Brichacek
authors.forename: S
authors.initials: S
authors.lastname: Goldstein
authors.forename: J
authors.initials: J
authors.lastname: Wakefield
authors.forename: R
authors.initials: R
authors.lastname: Byrum
authors.forename: W R
authors.initials: WR
authors.lastname: Elkins
authors.forename: B H
authors.initials: BH
authors.lastname: Hahn
authors.forename: J D
authors.initials: JD
authors.lastname: Lifson
authors.forename: M
authors.initials: M
authors.lastname: Stevenson
mesh_terms: D000818:Animals; D016665:Cercocebus atys; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007413:Intestinal Mucosa / Q000821:virology; D008254:Macaca nemestrina; D008264:Macrophages / Q000276:immunology* / Q000821:virology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D019562:Viral Load; D054334:Viral Regulatory and Accessory Proteins / Q000502:physiology*; D014779:Virus Replication
chemical_list: C513059:VPX protein, Simian immunodeficiency virus; D054334:Viral Regulatory and Accessory Proteins