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Pathogenesis of SIV encephalitis. Selection and replication of neurovirulent SIV
M C Zink1, A M Amedee, J L Mankowski
1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Abstract:
To investigate the viral and host factors that contribute to neurological disease, nine macaques were intravenously co-inoculated with SIV/DeltaB670, a primary isolate of SIV consisting of at least 21 different genotypes, and SIV/17E-Fr, a neurovirulent recombinant clone. CD4+ cell counts and antigenemia were measured throughout infection. The SIV env V1 region was amplified from brain and peripheral blood mononuclear cell DNA to compare the genotypes present in brain and blood. Seven of the 9 macaques (78%) developed typical SIV-associated neurological lesions classified as severe (4 macaques), moderate (2 macaques), or mild (1 macaque) with a mean time to euthanasia of 7 months. Macaques with severe neurological lesions progressed more rapidly, with a mean time to euthanasia of 3-6 months. SIV/17E-Fr was detected in brain homogenates from all four macaques with severe encephalitis, and in three of the four, SIV/17E-Fr was the only genotype identified in the central nervous system. Macaques with less severe or no neurological lesions usually had one of various genotypes of SIV/DeltaB670 in brain. A variety of genotypes of SIV/DeltaB670 and SIV/17E-Fr were detected in peripheral blood mononuclear cells throughout infection. Macaques with severe neurological lesions had the most precipitous declines in CD4+ cell counts, the highest levels of antigenemia, and the greatest expression of viral RNA and protein in the central nervous system. Macaca nemestrina were more likely to develop severe neurological lesions than M. mulatta or M. fascicularis (P = 0.048). This study demonstrated that neurovirulent strains within the virus swarm can selectively enter and become established in the central nervous system and that the neurological lesions that develop are correlated with the development of host immunosuppression. The species differences in severity of neurological lesions seen in this study suggest that host factors are also important in determining the outcome of lentiviral infection.
Insights
Neurovirulent simian immunodeficiency virus (SIV) strains selectively target the central nervous system, causing severe neurological disease correlated with host immunosuppression. Host factors also influence disease severity in macaques.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Neurological complications are significant in lentiviral infections.
- Understanding viral and host factors is crucial for predicting disease progression.
Purpose of the Study:
- To investigate viral and host factors contributing to SIV-induced neurological disease.
- To compare SIV genotypes in the brain and peripheral blood.
Main Methods:
- Nine macaques were co-inoculated with SIV/DeltaB670 and SIV/17E-Fr.
- CD4+ cell counts and antigenemia were monitored.
- SIV env V1 region genotypes were analyzed in brain and PBMCs.
Main Results:
- 78% of macaques developed SIV-associated neurological lesions.
- Severe encephalitis correlated with SIV/17E-Fr detection in the CNS.
- Rapid disease progression, lower CD4+ counts, and higher antigenemia were observed in severe cases.
- Macaca nemestrina showed higher susceptibility to severe neurological lesions.
Conclusions:
- Neurovirulent SIV strains can selectively establish in the CNS, driving neurological lesions.
- Neurological disease severity correlates with host immunosuppression.
- Host factors, including species, play a role in lentiviral neurological disease outcomes.