Dataset Information

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.

SUBMITTER: Filipowicz AR

PROVIDER: S-EPMC5017189 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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

Filipowicz Adam R AR McGary Christopher M CM Holder Gerard E GE Lindgren Allison A AA Johnson Edward M EM Sugimoto Chie C Kuroda Marcelo J MJ Kim Woong-Ki WK

Scientific reports 20160909

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 ...[more]

PMID: 27610547

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Project description:Latent viral reservoir is recognized as the major obstacle to achieving a functional cure for HIV infection. We previously reported that arsenic trioxide (As2O3) combined with antiretroviral therapy (ART) can reactivate the viral reservoir and delay viral rebound after ART interruption in chronically simian immunodeficiency virus (SIV)-infected macaques. In this study, we further investigated the effect of As2O3 independent of ART in chronically SIV-infected macaques. We found that As2O3-only treatment significantly increased the CD4/CD8 ratio, improved SIV-specific T cell responses, and reactivated viral latency in chronically SIVmac239-infected macaques. RNA-sequencing analysis revealed that As2O3 treatment downregulated the expression levels of genes related to HIV entry and infection, while the expression levels of genes related to transcription initiation, cell apoptosis, and host restriction factors were significantly upregulated. Importantly, we found that As2O3 treatment specifically induced apoptosis of SIV-infected CD4+ T cells. These findings revealed that As2O3 might not only impact viral latency, but also induce the apoptosis of HIV-infected cells and thus block the secondary infection of bystanders. Moreover, we investigated the therapeutic potential of this regimen in acutely SIVmac239-infected macaques and found that As2O3 + ART treatment effectively restored the CD4+ T cell count, delayed disease progression, and improved survival in acutely SIV-infected macaques. In sum, this work provides new insights to develop As2O3 as a component of the "shock-and-kill" strategy toward HIV functional cure. IMPORTANCE Although antiretroviral therapy (ART) can effectively suppress the viral load of AIDS patients, it cannot functionally cure HIV infection due to the existence of HIV reservoir. Strategies toward HIV functional cure are still highly anticipated to ultimately end the pandemic of AIDS. Herein, we investigated the direct role of As2O3 independent of ART in chronically SIV-infected macaques and explored the underlying mechanisms of the potential of As2O3 in the treatment of HIV/SIV infection. Meanwhile, we investigated the therapeutic effects of ART+As2O3 in acutely SIVmac239-infected macaques. This study showed that As2O3 has the potential to be launched into the "shock-and-kill" strategy to suppress HIV/SIV reservoir due to its latency-reversing and apoptosis-inducing properties.

Dataset Information

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

Publications

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

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