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Development and characterization of positively selected brain-adapted SIV
Peter J Gaskill1, Debbie D Watry, Tricia H Burdo
1Department of Neuropharmacology, The Scripps Research Institute, 10550 N, Torrey Pines Road, La Jolla, CA 92037, USA. walkin@scripps.edu
Abstract:
HIV is found in the brains of most infected individuals but only 30% develop neurological disease. Both viral and host factors are thought to contribute to the motor and cognitive disorders resulting from HIV infection. Here, using the SIV/rhesus monkey system, we characterize the salient characteristics of the virus from the brain of animals with neuropathological disorders. Nine unique molecular clones of SIV were derived from virus released by microglia cultured from the brains of two macaques with SIV encephalitis. Sequence analysis revealed a remarkably high level of similarity between their env and nef genes as well as their 3' LTR. As this genotype was found in the brains of two separate animals, and it encoded a set of distinct amino acid changes from the infecting virus, it demonstrates the convergent evolution of the virus to a unique brain-adapted genotype. This genotype was distinct from other macrophage-tropic and neurovirulent strains of SIV. Functional characterization of virus derived from representative clones showed a robust in vitro infection of 174xCEM cells, primary macrophages and primary microglia. The infectious phenotype of this virus is distinct from that shown by other strains of SIV, potentially reflecting the method by which the virus successfully infiltrates and infects the CNS. Positive in vivo selection of a brain-adapted strain of SIV resulted in a near-homogeneous strain of virus with distinct properties that may give clues to the viral basis of neuroAIDS.
Insights
Researchers identified a unique brain-adapted Simian Immunodeficiency Virus (SIV) genotype in macaques with neurological disease. This discovery offers insights into the viral factors driving neuroAIDS development.
Area of Science:
- Neurovirology
- Immunology
- Genetics
Background:
- Human Immunodeficiency Virus (HIV) infects the brain in most individuals, yet only 30% develop neurological disease.
- Both viral and host factors are implicated in HIV-associated motor and cognitive disorders.
Purpose of the Study:
- To characterize the viral characteristics of Simian Immunodeficiency Virus (SIV) in the brain of macaques exhibiting neuropathological disorders.
- To understand the viral basis of neuroAIDS by identifying specific SIV genotypes adapted to the central nervous system (CNS).
Main Methods:
- Isolation and molecular characterization of nine unique SIV clones from microglia of macaques with SIV encephalitis.
- Sequence analysis of env, nef genes, and 3' LTR to identify genetic similarities and differences.
- In vitro functional characterization of viral infectivity in various cell types (174xCEM, macrophages, microglia).
Main Results:
- A distinct SIV genotype with high similarity in env, nef, and 3' LTR was identified in two separate macaques.
- This brain-adapted genotype exhibited unique amino acid changes compared to the infecting virus, indicating convergent evolution.
- The identified SIV strain demonstrated robust in vitro infection of macrophages and microglia, differing from other SIV strains.
- In vivo selection resulted in a near-homogeneous, brain-adapted SIV strain with distinct properties.
Conclusions:
- Convergent evolution led to a unique, brain-adapted SIV genotype in macaques with neurological disease.
- This genotype possesses distinct infectious properties potentially facilitating CNS infiltration and infection.
- The findings provide crucial clues into the viral mechanisms underlying neuroAIDS.
