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Research Article

Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir

Claudia R. Avalos, Celina M. Abreu, Suzanne E. Queen, Ming Li, Sarah Price, Erin N. Shirk, Elizabeth L. Engle, Ellen Forsyth, Brandon T. Bullock, Feilim Mac Gabhann, Stephen W. Wietgrefe, Ashley T. Haase, M. Christine Zink, Joseph L. Mankowski, Janice E. Clements, Lucio Gama
Arturo Casadevall, Editor
Claudia R. Avalos
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Celina M. Abreu
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Suzanne E. Queen
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Ming Li
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Sarah Price
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Erin N. Shirk
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Elizabeth L. Engle
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Ellen Forsyth
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Brandon T. Bullock
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Feilim Mac Gabhann
e Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USA
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Stephen W. Wietgrefe
d Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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Ashley T. Haase
d Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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M. Christine Zink
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
b Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Joseph L. Mankowski
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
b Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
c Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Janice E. Clements
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
b Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
c Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Lucio Gama
a Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
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Arturo Casadevall
Johns Hopkins Bloomberg School of Public Health
Roles: Editor
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DOI: 10.1128/mBio.01186-17
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ABSTRACT

A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART.

IMPORTANCE Resting CD4+ T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4+ T cells and underscore the importance of macrophages in developing strategies to eradicate HIV.

  • Copyright © 2017 Avalos et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license .

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Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
Claudia R. Avalos, Celina M. Abreu, Suzanne E. Queen, Ming Li, Sarah Price, Erin N. Shirk, Elizabeth L. Engle, Ellen Forsyth, Brandon T. Bullock, Feilim Mac Gabhann, Stephen W. Wietgrefe, Ashley T. Haase, M. Christine Zink, Joseph L. Mankowski, Janice E. Clements, Lucio Gama
mBio Aug 2017, 8 (4) e01186-17; DOI: 10.1128/mBio.01186-17

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Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
Claudia R. Avalos, Celina M. Abreu, Suzanne E. Queen, Ming Li, Sarah Price, Erin N. Shirk, Elizabeth L. Engle, Ellen Forsyth, Brandon T. Bullock, Feilim Mac Gabhann, Stephen W. Wietgrefe, Ashley T. Haase, M. Christine Zink, Joseph L. Mankowski, Janice E. Clements, Lucio Gama
mBio Aug 2017, 8 (4) e01186-17; DOI: 10.1128/mBio.01186-17
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KEYWORDS

brain
macrophages
Simian Acquired Immunodeficiency Syndrome
simian immunodeficiency virus
Virus Latency
brain
human immunodeficiency virus
latency
macrophages
simian immunodeficiency virus

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