Pathogenicity and comparative evolution in vivo of the transitional quasispecies SIVsmmPBj8

During 14 months of infection of a pig-tailed macaque, the acutely lethal s imian immunodeficiency virus SIVsmmPBj14 (SIV-PBj14) evolved from the minim ally pathogenic strain SIVsmm9. The virus isolated at 8 months (SIV-PBj8) e xhibited properties of both SIVsmm9 and SIV-PBj14, indicating that a phenot ypic transition occurred between 6 and 10 months. To assess the influence t hat this new composition of biologic properties might have on pathogenicity , three pig-tailed macaques were inoculated intravenously with SIV-PBj8. Al though no animals developed the severe acute disease syndrome typical of SI V-PBj14, all had high levels of viremia and died of AIDS at 4, 10.5, and 32 months. Characterization of the SIV-PBj8-derived quasispecies that evolved in these macaques showed that at 4 days after inoculation, viruses from al l three animals exhibited in vitro properties different from those of the i noculum. By 4 months, the initial phenotypic profiles had changed, with the quasispecies in plasma from the animal (J90232) that died at this time mos t closely resembling SIV-PBj14, not SIV-PBj8. Phylogenetic trees of the gp4 1/Nef region of viruses in 4-month plasma from J90232 revealed three distin ct populations with high bootstrap values: one group branched with SIVsmm9, one with SIV-PBj14, and one with SIV-PBj8 (ratio of clones, 5:9:5). Nucleo tide sequence analysis suggested that some members of the original SIV-PBj8 quasispecies may have been evolving toward a SIV-PBj14-like genotype at th e time macaque J90232 died. The use of SIV-PBj8, which was more pathogenic than SIVsmm9, but less pathogenic than SIV-PBj14, may provide the optimal g enetic background on which to identify the minimal, multigenic determinants of the SIV-PBj14 phenotype. The results of our studies on SIV-PBj14 indica te that in some, but not all, cases of primate lentivirus infection more pa thogenic variants evolve, selectively proliferate, and more than likely con tribute to disease progression. (C) 1999 Academic Press.