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Pathogenicity and comparative evolution in vivo of the transitional quasispecies SIVsmmPBj8
1Department of Microbiology, University of Alabama School of Medicine, Birmingham, Alabama 35294, USA.
Abstract:
During 14 months of infection of a pig-tailed macaque, the acutely lethal simian immunodeficiency virus SIVsmmPBj14 (SIV-PBj14) evolved from the minimally pathogenic strain SIVsmm9. The virus isolated at 8 months (SIV-PBj8) exhibited properties of both SIVsmm9 and SIV-PBj14, indicating that a phenotypic transition occurred between 6 and 10 months. To assess the influence that this new composition of biologic properties might have on pathogenicity, three pig-tailed macaques were inoculated intravenously with SIV-PBj8. Although no animals developed the severe acute disease syndrome typical of SIV-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 all three animals exhibited in vitro properties different from those of the inoculum. By 4 months, the initial phenotypic profiles had changed, with the quasispecies in plasma from the animal (J90232) that died at this time most closely resembling SIV-PBj14, not SIV-PBj8. Phylogenetic trees of the gp41/Nef region of viruses in 4-month plasma from J90232 revealed three distinct 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). Nucleotide sequence analysis suggested that some members of the original SIV-PBj8 quasispecies may have been evolving toward a SIV-PBj14-like genotype at the 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 genetic background on which to identify the minimal, multigenic determinants of the SIV-PBj14 phenotype. The results of our studies on SIV-PBj14 indicate that in some, but not all, cases of primate lentivirus infection more pathogenic variants evolve, selectively proliferate, and more than likely contribute to disease progression.
Insights
Simian immunodeficiency virus SIV-PBj8 evolved towards a more pathogenic SIV-PBj14-like genotype in macaques, leading to AIDS. This study investigates viral evolution and pathogenicity in primate lentivirus infections.
Area of Science:
- Virology
- Immunology
- Primate Models
Background:
- Simian immunodeficiency virus (SIV) infection in macaques serves as a model for human immunodeficiency virus (HIV) pathogenesis.
- The acutely lethal SIVsmmPBj14 (SIV-PBj14) strain evolved from a less pathogenic SIVsmm9 strain during a 14-month macaque infection.
- An intermediate strain, SIV-PBj8, isolated at 8 months, exhibited properties of both parent strains, indicating a significant phenotypic transition.
Purpose of the Study:
- To assess the pathogenicity of the intermediate SIV-PBj8 strain.
- To characterize the evolution of SIV-PBj8 quasispecies in vivo.
- To identify genetic determinants of SIV-PBj14 pathogenicity by using SIV-PBj8 as a model.
Main Methods:
- Intravenous inoculation of three pig-tailed macaques with SIV-PBj8.
- Monitoring of viremia and survival.
- In vitro characterization of viral quasispecies.
- Phylogenetic analysis and nucleotide sequencing of viral populations.
Main Results:
- All inoculated macaques developed high viremia and died of AIDS at various time points (4, 10.5, and 32 months).
- Viral quasispecies in macaques rapidly evolved distinct in vitro properties compared to the inoculum.
- By 4 months post-inoculation, the quasispecies in one macaque closely resembled the highly pathogenic SIV-PBj14.
- Phylogenetic analysis revealed the emergence of SIV-PBj14-like viral populations within the SIV-PBj8 quasispecies.
Conclusions:
- SIV-PBj8, while less pathogenic than SIV-PBj14, can induce AIDS in macaques.
- Viral evolution towards more pathogenic genotypes occurs during primate lentivirus infections.
- The SIV-PBj8 quasispecies provides a valuable model for dissecting the genetic basis of SIV-PBj14 pathogenicity.