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Progressive selection for neurovirulent genotypes in the brain of SIV-infected macaques
Tahar Babas1, Jesse B Dewitt, Joseph L Mankowski
1Department of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Objective:
To compare the viral genotypes present in RNA from brain and peripheral blood mononuclear cells (PBMC) and DNA from brain during acute, asymptomatic and late stages of SIV infection of macaques.
Methods:
Eighteen pigtailed macaques were intravenously inoculated with SIV. At 10, 21 and 56 days postinoculation, six were euthanized and the severity of encephalitis was assessed by microscopic examination. DNA and RNA were isolated from brain and PBMC, and the V1 region of env was amplified by the polymerase chain reaction and sequenced from over 800 different clones.
Results:
Similar genotypes were detected in RNA from brain and PBMC at 10 days postinoculation, suggesting an unrestricted exchange of virus between the periphery and the brain during acute infection. There was a progressive increase in the percentage of neurovirulent genotypes in brain RNA from acute (14% of all genotypes detected in brain RNA) to early asymptomatic (45%), to late asymptomatic (52%) and to terminal (95%) infection. Fewer different genotypes were found in brain RNA than in PBMC RNA from macaques euthanized during early asymptomatic (2.5 and 5 different genotypes, respectively; P = 0.007), late asymptomatic (2 and 5 different genotypes, respectively; P = 0.003) and terminal (2 and 4 different genotypes, respectively; P < 0.001) infection.
Conclusion:
These data demonstrate that the almost exclusive replication of neurovirulent genotypes in the brain seen at late-stage infection is a progressive process that begins early in infection and continues to late stage disease.
Insights
Neurovirulent simian immunodeficiency virus (SIV) genotypes progressively increase in macaque brains during infection. This shift from diverse peripheral genotypes to dominant neurovirulent ones begins early and continues throughout the disease progression.
Area of Science:
- Virology
- Neuroscience
- Immunology
Background:
- Simian immunodeficiency virus (SIV) infection in macaques serves as a model for studying human immunodeficiency virus (HIV) pathogenesis.
- Understanding viral evolution within the central nervous system (CNS) is critical for developing effective therapies against SIV/HIV-associated neurological complications.
Purpose of the Study:
- To compare viral genotypes in RNA from brain and peripheral blood mononuclear cells (PBMC) and DNA from brain during acute, asymptomatic, and late stages of SIV infection in macaques.
Main Methods:
- Eighteen pigtailed macaques were inoculated with SIV.
- Viral RNA and DNA were isolated from brain and PBMC at 10, 21, and 56 days post-inoculation.
- The V1 region of the SIV env gene was amplified and sequenced from over 800 clones to analyze viral genotypes.
Main Results:
- Viral genotypes in brain and PBMC RNA were similar during acute infection, indicating unrestricted viral exchange.
- A progressive increase in neurovirulent genotypes was observed in brain RNA, rising from 14% in acute to 95% in terminal infection.
- Fewer distinct viral genotypes were found in brain RNA compared to PBMC RNA during later stages of infection.
Conclusions:
- The predominance of neurovirulent SIV genotypes in the brain is a gradual process starting early in infection.
- This genotypic shift contributes to the development of SIV encephalitis and highlights the importance of early therapeutic interventions.
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