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Simian immunodeficiency virus encephalitis: analysis of envelope sequences from individual brain multinucleated giant
Elena V Ryzhova1, Peter Crino, Linda Shawver
1Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Abstract:
Simian immunodeficiency virus (SIV)-infected macaques develop an encephalitis (SIVE) that is pathologically virtually indistinguishable from that associated with HIV infection, with multinucleated giant cells (MNGCs) being the principal histopathological manifestation. To dissect SIV variants responsible for MNGC development, we examined the relationships between env sequences transcribed in individual MNGCs and those from genomic DNA of brain and spleen tissues. The brain-specific variant found in all brain clones was dominant among the clones from MNGCs, suggesting a role in the formation of giant cells. Furthermore, two additional minor groups of sequences were present in MNGCs. One group consisted of sequences closely related to those from spleen, indicating recent and probably multiple episodes of neuroinvasion. The second group represented clones similar or identical to the initial inoculum. The survival of archival sequences and their activation presumably by the fusion of productively and quiescently infected macrophages/microglia identify the central nervous system as a possible anatomical reservoir for latent infection.
Insights
Simian immunodeficiency virus (SIV) infection in macaques causes encephalitis with multinucleated giant cells (MNGCs). A brain-specific SIV variant drives MNGC formation, revealing the central nervous system as a potential reservoir for latent infection.
Area of Science:
- Neurovirology
- Immunodeficiency Virus Research
- Pathology
Background:
- Simian immunodeficiency virus (SIV) infection in macaques recapitulates human immunodeficiency virus (HIV) infection, including the development of SIV encephalitis (SIVE).
- Multinucleated giant cells (MNGCs) are the hallmark histopathological feature of SIVE, similar to HIV encephalitis.
Purpose of the Study:
- To investigate the specific SIV env variants associated with MNGC formation in the brain.
- To understand the origin and dynamics of SIV within the central nervous system (CNS) during encephalitis.
Main Methods:
- Analysis of SIV env gene sequences from individual MNGCs in brain tissue.
- Comparison of brain-derived SIV sequences with those from genomic DNA of brain and spleen tissues.
- Phylogenetic analysis to identify distinct SIV variants and their relationships.
Main Results:
- A dominant brain-specific SIV variant was identified in MNGCs, strongly implicating it in giant cell formation.
- Minor SIV sequence groups in MNGCs were related to spleen-derived sequences, suggesting recent neuroinvasion events.
- Archival SIV sequences, potentially reactivated, were found, indicating the CNS as a reservoir.
Conclusions:
- The CNS harbors distinct SIV variants, with a brain-adapted strain driving MNGC formation in SIVE.
- Evidence suggests multiple episodes of neuroinvasion and the CNS's role as a sanctuary for latent SIV infection.
- Understanding these viral dynamics is crucial for developing therapeutic strategies against SIV/HIV-associated neuroinflammation.