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.
Highlights
It is conventionally believed that macrophages are terminally differentiated cells that are in the G0 stage of the cell cycle and do not proliferate[6,7], thereby implying that macrophage accumulation in tissues is solely due to the contribution from infiltrating monocytes
We examined the expression of cell cycle proteins (Ki-67, cyclin D1, and p16INK4a), by immunohistochemistry, in the frontal and/or temporal cortices and brainstems of uninfected control macaques (n = 3), simian immunodeficiency virus (SIV)-infected macaques without encephalitis (SIVnoE, n = 4), and SIV-infected macaques with encephalitis (SIVE, n = 4) (Table 1)
A very similar pattern of expression of other cell cycle markers including proliferating cell nuclear antigen (PCNA) and minichromosome maintenance complex component 2 (MCM2) was observed (Fig. S2). Based on their association with inflammatory perivascular cuffs and encephalitic lesions, we suspected that cells positive for these cell cycle proteins were of the macrophage lineage
Summary
It is conventionally believed that macrophages are terminally differentiated cells that are in the G0 stage of the cell cycle and do not proliferate[6,7], thereby implying that macrophage accumulation in tissues is solely due to the contribution from infiltrating monocytes. Recent mouse studies have demonstrated that macrophages do proliferate locally during inflammation[8,9,10,11] These studies, using in vivo thymidine analog incorporation and Ki-67 co-localization, found that local macrophage proliferation dominates lesion formation and inflammation, independently of monocyte recruitment, in the pleural cavity, arterial intima, and adipose tissue. HIVE patient samples stained for Ki-67 and CD68 show evidence of proliferating PVM These findings indicate that local PVM proliferation contributes to macrophage accumulation and lesion growth and may be one of the underlying mechanisms of HIV/SIV persistence in the CNS
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