Proliferation of Perivascular Macrophages Contributes to the Development of Encephalitic Lesions in HIV-Infected Humans and in SIV-Infected Macaques
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Published on: September 5, 2016
Adam R Filipowicz1, Christopher M McGary1, Gerard E Holder1
1Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia, United States.
Abstract:
The aim of the present study was to investigate if macrophage proliferation occurs in the brain during simian immunodeficiency virus (SIV) infection of adult macaques. We examined the expression of the Ki-67 proliferation marker in the brains of uninfected and SIV-infected macaques with or without encephalitis. Double-label immunohistochemistry using antibodies against the pan-macrophage marker CD68 and Ki-67 showed that there was a significant increase in CD68+Ki-67+ cells in macaques with SIV encephalitis (SIVE) compared to uninfected and SIV-infected animals without encephalitis, a trend that was also confirmed in brain samples from patients with HIV encephalitis. Multi-label immunofluorescence for CD163 and Ki-67 confirmed that the vast majority of Ki-67+ nuclei were localized to CD163+ macrophages in perivascular cuffs and lesions. The proliferative capacity of Ki-67+ perivascular macrophages (PVM) was confirmed by their nuclear incorporation of bromodeoxyuridine. Examining SIVE lesions, using double-label immunofluorescence with antibodies against SIV-Gag-p28 and Ki-67, showed that the population of Ki-67+ cells were productively infected and expanded proportionally with lesions. Altogether, this study shows that there are subpopulations of resident PVM that express Ki-67 and are SIV-infected, suggesting a mechanism of macrophage accumulation in the brain via PVM proliferation.
Insights
Macrophage proliferation occurs in the brain during simian immunodeficiency virus (SIV) infection, contributing to SIV encephalitis (SIVE). This study reveals resident perivascular macrophages (PVM) proliferate and become SIV-infected, driving SIVE pathogenesis.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Simian immunodeficiency virus (SIV) infection in macaques serves as a model for human immunodeficiency virus (HIV) infection.
- Brain inflammation and neurological complications, such as encephalitis, are significant challenges in SIV and HIV infections.
Purpose of the Study:
- To investigate whether macrophage proliferation occurs in the brain during SIV infection.
- To determine if proliferating macrophages are infected with SIV and contribute to SIV encephalitis (SIVE).
Main Methods:
- Examined brain tissue from uninfected and SIV-infected macaques using immunohistochemistry and immunofluorescence.
- Utilized markers such as Ki-67 (proliferation), CD68 and CD163 (macrophages), and SIV-Gag-p28 (SIV infection).
- Assessed bromodeoxyuridine incorporation to confirm proliferative capacity of perivascular macrophages (PVM).
Main Results:
- A significant increase in CD68+Ki-67+ cells was observed in macaques with SIVE compared to controls.
- The majority of proliferating cells (Ki-67+) in SIVE lesions were identified as CD163+ macrophages.
- Proliferating PVM were found to be productively infected with SIV and expanded proportionally with lesion size.
Conclusions:
- Macrophage proliferation is a key mechanism contributing to macrophage accumulation in the brain during SIV infection.
- Subpopulations of resident PVM are capable of proliferation and become infected with SIV, driving SIVE pathogenesis.
- Findings suggest therapeutic strategies targeting macrophage proliferation could be beneficial for managing SIVE and HIV encephalitis.
