title: The tyrosine-17 residue of Nef in SIVsmmPBj14 is required for acute pathogenesis and contributes to replication in macrophages.
abstract: The variant simian immunodeficiency virus termed SIVsmmPBj14 induces a rapidly fatal disease in pig-tailed macaques. The acute pathogenic effects of this virus appear to be associated with at least two in vitro characteristics: the ability to induce lymphocyte proliferation; and the ability to replicate in unstimulated PBMC. Two of the amino acids in Nef of PBj14 (the No. 17 residue, tyrosine, and the No. 18 residue, glutamic acid) appear to be linked to the virus' ability to induce lymphocyte activation. To further study the effects of these amino acids on PBj14-induced pathogenesis, we generated two mutant viruses from our molecular clone, PBj6.6, containing either changes in both the No. 17 and No. 18 residues (termed PBj6.6YE-RQ), or a single change in the No. 17 residue (termed PBj6.6Y-R). In vitro analyses of these viruses showed that while their replicative abilities in stimulated peripheral blood mononuclear cells (PBMC) were altered, they still maintained the ability to replicate in unstimulated PBMC. Replication of these viruses in macrophage populations was impaired relative to the wild-type virus. Both mutant viruses were unable to induce proliferation of macaque PBMC in vitro. Virus derived from PBj6.6Y-R was unable to induce acute disease in macaques, but did maintain the ability to induce lymphopenia and intestinal lymphoid hyperplasia. These results show that the tyrosine-17 residue of Nef is linked to lymphocyte proliferation and disease development, but also suggest that the pathogenic characteristics of SIVsmmPBj14 are dependent upon multiple genetic determinants.
authors.affiliation: Division of Microbiology and Immunology, Yerkes Regional Primate Research Center, Atlanta, Georgia, USA.
authors.forename: M
authors.initials: M
authors.lastname: Saucier
authors.forename: S
authors.initials: S
authors.lastname: Hodge
authors.forename: S
authors.initials: S
authors.lastname: Dewhurst
authors.forename: T
authors.initials: T
authors.lastname: Gibson
authors.forename: J P
authors.initials: JP
authors.lastname: Gibson
authors.forename: H M
authors.initials: HM
authors.lastname: McClure
authors.forename: F J
authors.initials: FJ
authors.lastname: Novembre
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D015693:Gene Products, nef / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D015754:Genes, nef; D014644:Genetic Variation; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008254:Macaca nemestrina; D008264:Macrophages / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000209:etiology; D015302:Simian Immunodeficiency Virus / Q000235:genetics* / Q000472:pathogenicity* / Q000502:physiology; D014443:Tyrosine / Q000737:chemistry; D014779:Virus Replication / Q000235:genetics
chemical_list: D017931:DNA Primers; D015693:Gene Products, nef; D014443:Tyrosine