Proliferation of Perivascular Macrophages Contributes to the Development of Encephalitic Lesions in HIV-Infected Humans and in SIV-Infected Macaques

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.

Overexpression and activation of colony‐stimulating factor 1 receptor in the SIV/macaque model of HIV infection and neuroHIV

“…Our current study indicates that PVMs express much higher levels of CSF1R than resting ramified microglia, and provides the first in vivo evidence that HIV/SIV infection of the CNS induces further upregulation and activation (measured by phosphorylation of CSF1R and STAT5) of CSF1R in PVM and activated microglia but not in resting microglia. Previously, we found increased proliferation of brain macrophages in HIV and SIV encephalitis, in line with these new findings regarding CSF1R signaling in the brain, correlating with the severity of SIV encephalitis .…”

Brain perivascular macrophages: Recent advances and implications in health and diseases

“…However, 69.9% of the PVMs were present in the CNS before SIVE lesion formation, suggesting the resident PVMs were the primary targets of SIV . Ki‐67 + proliferating PVMs were identifiable in both HIV‐infected human brains and SIV‐infected macaque brains, confirming the proliferation of productively infected PVMs …”

Brain perivascular macrophages: characterization and functional roles in health and disease

“…However, over 80% of the PVM in the lesions are present in the brain before development of pathology, suggesting that brain-resident PVM, rather than peripheral monocytes recruited into the lesion, are targeted by the infection [51]. In this context, cells expressing Ki-67, a marker of cell proliferation, were found in SIV lesions [52]. The majority of these cells were CD163 + and were localized perivascularly [52].…”

“…In this context, cells expressing Ki-67, a marker of cell proliferation, were found in SIV lesions [52]. The majority of these cells were CD163 + and were localized perivascularly [52]. Therefore, proliferation of PVM, rather than recruitment of monocytes from the periphery, could be the primary mechanism of encephalitic lesion formation and persistence of the viral reservoir in the brain [52].…”