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

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...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	brain human immunodeficiency virus latency macrophages simian immunodeficiency virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/cc2e12c107704e4d86a6f1bc8f4383ea
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spelling	oai:doaj.org-article:cc2e12c107704e4d86a6f1bc8f4383ea2021-11-15T15:51:43ZBrain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir10.1128/mBio.01186-172150-7511https://doaj.org/article/cc2e12c107704e4d86a6f1bc8f4383ea2017-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01186-17https://doaj.org/toc/2150-7511ABSTRACT 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.Claudia R. AvalosCelina M. AbreuSuzanne E. QueenMing LiSarah PriceErin N. ShirkElizabeth L. EngleEllen ForsythBrandon T. BullockFeilim Mac GabhannStephen W. WietgrefeAshley T. HaaseM. Christine ZinkJoseph L. MankowskiJanice E. ClementsLucio GamaAmerican Society for Microbiologyarticlebrainhuman immunodeficiency viruslatencymacrophagessimian immunodeficiency virusMicrobiologyQR1-502ENmBio, Vol 8, Iss 4 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	brain human immunodeficiency virus latency macrophages simian immunodeficiency virus Microbiology QR1-502
spellingShingle	brain human immunodeficiency virus latency macrophages simian immunodeficiency virus Microbiology QR1-502 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 Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
description	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.
format	article
author	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
author_facet	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
author_sort	Claudia R. Avalos
title	Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
title_short	Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
title_full	Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
title_fullStr	Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
title_full_unstemmed	Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
title_sort	brain macrophages in simian immunodeficiency virus-infected, antiretroviral-suppressed macaques: a functional latent reservoir
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/cc2e12c107704e4d86a6f1bc8f4383ea
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Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir

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