Biologic studies of chimeras of highly and moderately virulent molecular clones of simian immunodeficiency virus SIVsmPBj suggest a critical role forenvelope in acute AIDS virus pathogenesis

Previous studies identified three molecular clones of the acutely pathogeni c SIVsmPBj strain that varied in terms of relative in vivo pathogenicity. O ne clone, SIVsmPBj6.6, reproducibly induced a rapidly fatal disease in pigt ailed macaques. In contrast, a highly related clone (SIVsmPBj6.9) was only minimally pathogenic in macaques. PBj6.6 and PBj6.9 shared a tyrosine subst itution at position 17 in the Nef protein that is a major determinant of vi rulence but differed at one residue in Vpx (C89R), three residues within th e envelope (D119G, R871G, G872R), and a single residue in Nef (F252L). SIVs mPBj6.9 was less efficient in inducing proliferation of resting macaque per ipheral blood mononuclear cells in vitro than SIVsmPBj6.6 and exhibited a m arked reduction in infectivity relative to SIVsmPBj6.6. Chimeric viruses fo r each of these variable residues were constructed, and their biologic prop erties were compared to those of the parental strains. Differences in Vpx a nd Nef did not alter the basic biologic phenotype of the chimeras. However, the D119G substitution in the envelope of SIVsmPBj6.9 was associated with a marked reduction in the infectivity of this virus relative to SIVsmPB6.6 An associated processing defect in gp160 of SIVsmPBj6.9 and chimeras expres sing the D119G substitution suggests that a reduction in virion envelope in corporation is the mechanistic basis for reduced virion infectivity. In viv o studies revealed that substitution of the PBj6.9 amino acid into PBj6.6 ( D119) abrogated the pathogenicity of this previously pathogenic virus. Intr oduction of the PBj6.9 G119, however, did not confer full virulence to the parental PBj6.9 virus, implicating one or all of the other four substitutio ns in the virulence of SIVsmPBj6.6.