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Isolation and characterization of a neuropathogenic simian immunodeficiency virus derived from a sooty mangabey
F J Novembre1, J De Rosayro, S P O'Neil
1Divisions of Microbiology and Immunology, Yerkes Regional Primate Research Center, School of Medicine, Emory University, Atlanta, Georgia 30322, USA. fnovembr@rmy.emory.edu
Abstract:
Transfusion of blood from a simian immunodeficiency virus (SIV)- and simian T-cell lymphotropic virus-infected sooty mangabey (designated FGb) to rhesus and pig-tailed macaques resulted in the development of neurologic disease in addition to AIDS. To investigate the role of SIV in neurologic disease, virus was isolated from a lymph node of a pig-tailed macaque (designated PGm) and the cerebrospinal fluid of a rhesus macaque (designated ROn2) and passaged to additional macaques. SIV-related neuropathogenic effects were observed in 100% of the pig-tailed macaques inoculated with either virus. Lesions in these animals included extensive formation of SIV RNA-positive giant cells in the brain parenchyma and meninges. Based upon morphology, the majority of infected cells in both lymphoid and brain tissue appeared to be of macrophage lineage. The virus isolates replicated very well in pig-tailed and rhesus macaque peripheral blood mononuclear cells (PBMC) with rapid kinetics. Differential replicative abilities were observed in both PBMC and macrophage populations, with viruses growing to higher titers in pig-tailed macaque cells than in rhesus macaque cells. An infectious molecular clone of virus derived from the isolate from macaque PGm (PGm5.3) was generated and was shown to have in vitro replication characteristics similar to those of the uncloned virus stock. While molecular analyses of this virus revealed its similarity to SIV isolates from sooty mangabeys, significant amino acid differences in Env and Nef were observed. This virus should provide an excellent system for investigating the mechanism of lentivirus-induced neurologic disease.
Insights
Simian immunodeficiency virus (SIV) infection in macaques caused AIDS and neurological disease. This study isolated SIV strains that consistently induced neuropathology, offering a model for lentivirus-induced brain disease.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Transfusion of blood from infected sooty mangabeys led to AIDS and neurological disease in macaques.
- The role of simian immunodeficiency virus (SIV) in this neurological disease required further investigation.
Purpose of the Study:
- To investigate the neuropathogenic potential of SIV isolates.
- To establish an animal model for studying lentivirus-induced neurologic disease.
Main Methods:
- Isolation and passage of SIV from infected macaques (pig-tailed and rhesus).
- Inoculation of macaques with SIV isolates to assess neuropathologic effects.
- Molecular cloning of SIV (PGm5.3) and in vitro replication studies in peripheral blood mononuclear cells (PBMCs) and macrophages.
Main Results:
- SIV inoculation caused neurologic disease in 100% of pig-tailed macaques, with lesions including SIV RNA-positive giant cells in the brain.
- Infected cells were primarily of macrophage lineage in both lymphoid and brain tissues.
- SIV isolates replicated efficiently in macaque PBMCs, with higher titers in pig-tailed macaque cells.
- The SIV clone PGm5.3 exhibited similar in vitro replication characteristics to the uncloned virus.
Conclusions:
- SIV is directly implicated in causing neuropathologic effects in macaques.
- The generated SIV isolates and clone provide a valuable system for studying the mechanisms of lentivirus-induced neurologic disease.
- Significant amino acid differences in Env and Nef were noted compared to other SIV isolates.