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Early brain injury in the SIV-macaque model of AIDS
R G González1, L L Cheng, S V Westmoreland
1Neuradiology Division, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Objective:
To specify the type and severity of cellular damage in the central nervous system soon after infection and at later stages of disease in the SIV-macaque model of AIDS.
Design And Methods:
Adjacent samples of frontal cortical gray matter were taken from three groups of macaques: uninfected controls (n = 4), acute (14 days post-infection; n = 4), and chronic (mean 2 years post-infection; n = 7). In vitro high resolution magnetic resonance spectroscopy of snap frozen intact tissue and quantitative neuropathology measurements of synaptophysin, calbindin, and glial fibrillary acidic protein (GFAP) in formalin-fixed tissue were performed.
Results:
Losses in n-acetylaspartate and calbindin (indicating neuronal injury and/or death) and decreases in synaptophysin immunoreactivity (indicating synaptodendritic injury) were detected along with increases in GFAP (indicating reactive gliosis). Cellular injury worsened progressively with increased time after infection.
Conclusions:
These results are the first direct evidence that neuronal injury occurs soon after infection. The exacerbation of injury with time suggests a connection between the early response of the central nervous system and dementia, which occurs late in the course of infection. This connection may have broad implications for the study of and the development of therapies for damage of the central nervous system by HIV.
Insights
Central nervous system (CNS) damage, including neuronal injury and reactive gliosis, occurs early after SIV infection in macaques and worsens over time, suggesting a link to late-stage dementia.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Acquired Immunodeficiency Syndrome (AIDS) dementia complex is a significant neurological complication of Human Immunodeficiency Virus (HIV) infection.
- The SIV-macaque model is crucial for understanding HIV neuropathogenesis.
- Early cellular damage in the central nervous system (CNS) following infection is not well characterized.
Purpose of the Study:
- To characterize the type and severity of CNS cellular damage in the SIV-macaque model at acute and chronic stages of infection.
- To investigate the temporal progression of neuropathology.
Main Methods:
- Analysis of frontal cortical gray matter from uninfected, acutely infected (14 days post-infection), and chronically infected (2 years post-infection) macaques.
- In vitro high-resolution magnetic resonance spectroscopy (MRS) of snap-frozen tissue.
- Quantitative neuropathology assessing synaptophysin, calbindin, and glial fibrillary acidic protein (GFAP) in formalin-fixed tissue.
Main Results:
- Neuronal injury/death indicated by losses in n-acetylaspartate and calbindin.
- Synaptodendritic injury shown by decreased synaptophysin immunoreactivity.
- Reactive gliosis evidenced by increased GFAP.
- Progressive worsening of cellular injury with increased time post-infection.
Conclusions:
- Direct evidence of early neuronal injury post-SIV infection.
- Exacerbation of CNS injury over time suggests a link between early infection response and late-stage dementia.
- Findings have implications for understanding and treating HIV-associated CNS damage.