Impact of various simian immunodeficiency virus variants on induction and nature of neuropathology in macaques
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1Pathologisches Institut, Universität Würzburg, Germany.
Abstract:
To investigate the possible influence of virus tropism on SIV-induced neuropathogenesis, macaques were infected with molecularly cloned SIVmac239 which replicates poorly in cultured macrophages, with SIVmac251/32H which is a macrophage-tropic biologic clone, and with SIVmac251/MPBMC which is an early passage of 32H with enhanced replication competence in macrophages. We found that inflammatory as well as neuropathologic changes were identical in all clinically affected animals, irrespective of the in vitro tropism of the inocula. Moribund animals exhibited SIV encephalitis characterized by overt infection of macrophages/microglia inside the CNS parenchyma. Additionally, neuropathology of moribund animals was characterized by extraparenchymal immunopathology (meninges, perivascular space, choroid plexus stroma) and subtle white matter degeneration with glial changes, often associated with infected macrophages in situ (except in leukoencephalopathy). However, in animals inoculated with the lymphocyte-tropic and enhanced macrophage-tropic inocula, microglia but not blood-derived macrophages were the primary cells infected. Altogether, our results underline the significance of macrophage infection for the development of SIV encephalitis, and suggest that SIVmac239 either undergoes a change in cell tropism in vivo that results in the ability to replicate in macrophages, or else macrophages become more permissive to infection by this virus in the terminal stage of immunosuppressive disease.
Insights
Virus tropism does not alter SIV-induced neuropathogenesis. Macrophage infection is key for developing SIV encephalitis, suggesting viral adaptation or increased host susceptibility in later disease stages.
Area of Science:
- Neuroscience
- Virology
- Immunology
Background:
- Understanding simian immunodeficiency virus (SIV) neuropathogenesis is crucial for human immunodeficiency virus (HIV) research.
- Virus tropism, the ability to infect specific cell types, may influence disease progression.
- The role of macrophage tropism in SIV-induced central nervous system (CNS) disease requires further investigation.
Purpose of the Study:
- To determine if virus tropism impacts SIV-induced neuropathogenesis in macaques.
- To elucidate the cellular targets of SIV infection within the CNS.
- To explore the relationship between viral replication in macrophages and the development of SIV encephalitis.
Main Methods:
- Macaques were infected with distinct SIVmac clones varying in macrophage tropism: SIVmac239 (poor macrophage replication), SIVmac251/32H (macrophage-tropic), and SIVmac251/MPBMC (enhanced macrophage replication).
- Clinical, neuropathological, and virological assessments were performed on infected animals.
- Cellular tropism of SIV within the CNS was analyzed, focusing on macrophages and microglia.
Main Results:
- Neuropathological and inflammatory changes were consistent across all clinically affected animals, regardless of the initial in vitro virus tropism.
- SIV encephalitis was characterized by macrophage/microglia infection within the CNS parenchyma and extraparenchymal immunopathology.
- In animals infected with lymphocyte-tropic or enhanced macrophage-tropic inocula, microglia, rather than blood-derived macrophages, were the primary infected cells within the CNS.
Conclusions:
- Macrophage infection plays a significant role in the development of SIV encephalitis.
- SIVmac239 may alter its cell tropism in vivo to infect macrophages, or macrophages may become more susceptible to infection in the terminal stages of immunosuppressive disease.
- These findings highlight the complex interplay between viral adaptation and host factors in SIV neuropathogenesis.