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Early viral replication in the brain of SIV-infected rhesus monkeys
L Chakrabarti1, M Hurtrel, M A Maire
1Unité d'Oncologie Virale, Institut Pasteur, Paris, France.
Abstract:
To investigate the mechanism of simian immunodeficiency virus (SIV) entry into the central nervous system (CNS) and the initial events leading to neuropathogenesis, SIV replication was studied by in situ hybridization in the CNS of 5 Rhesus macaques at 7 days, 1, 2, and 3 months after SIV intravenous inoculation. CNS infection was found to be a frequent and early event, as SIV was detected in the CNS of all the animals studied and as early as 7 days postinoculation. At the earliest stage, the infection localized mainly to perivascular cells. Using combined immunohistochemistry and in situ hybridization, infected cells were shown to express the CD68 marker, suggesting that infected mononuclear phagocytes crossing the blood-brain barrier represent the main source of virus in the CNS. Early viral replication coincided with neuropathologic changes, consisting in gliosis, perivascular infiltrates and rare glial nodules. Immunophenotyping of brain tissue showed that increased macrophage infiltration, microglial reactivity and MHC class II induction occurred within the first week of infection, indicating a possible immunopathologic mechanism in early CNS pathogenesis.
Insights
Simian immunodeficiency virus (SIV) frequently and early infects the central nervous system (CNS) primarily via infected mononuclear phagocytes. This early SIV invasion triggers neuropathogenesis and immune responses within the brain.
Area of Science:
- Neurovirology
- Immunology
- Pathogenesis
Background:
- Simian immunodeficiency virus (SIV) entry into the central nervous system (CNS) and subsequent neuropathogenesis remain incompletely understood.
- Investigating early viral events is crucial for understanding SIV-induced brain damage.
Purpose of the Study:
- To elucidate the mechanism of SIV entry into the CNS.
- To identify the initial events leading to SIV-related neuropathogenesis.
Main Methods:
- In situ hybridization and immunohistochemistry were employed to detect SIV replication in the CNS of Rhesus macaques.
- Immunophenotyping was used to analyze cellular changes in the brain tissue.
Main Results:
- SIV infection was detected in all animals studied, as early as 7 days post-inoculation, localizing to perivascular cells.
- Infected cells expressed CD68, indicating mononuclear phagocytes as the primary source of SIV in the CNS.
- Early viral replication correlated with neuropathologic changes like gliosis and perivascular infiltrates, alongside increased macrophage infiltration and microglial reactivity.
Conclusions:
- Mononuclear phagocytes crossing the blood-brain barrier are the main source of early SIV CNS infection.
- Early SIV infection initiates neuropathogenesis through immunopathologic mechanisms involving glial activation and inflammation.