Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS

ABSTRACT Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not...

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Autores principales:	Cheri A. Lee, Erin Beasley, Karthikeyan Sundar, Margery Smelkinson, Carol Vinton, Claire Deleage, Kenta Matsuda, Fan Wu, Jake D. Estes, Bernard A. P. Lafont, Jason M. Brenchley, Vanessa M. Hirsch
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	AIDS CD4 T cells central nervous system infections encephalitis inflammation macrophages Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/40f2856af6be4f2a8fb0aa9a0ec10809
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spelling	oai:doaj.org-article:40f2856af6be4f2a8fb0aa9a0ec108092021-11-15T15:57:01ZSimian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS10.1128/mBio.00602-202150-7511https://doaj.org/article/40f2856af6be4f2a8fb0aa9a0ec108092020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00602-20https://doaj.org/toc/2150-7511ABSTRACT Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4+ T cells (CD4) and macrophages (MΦs) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4+ memory T cells (Br-mCD4), brain-MΦs (Br-MΦs), and brain B cells (Br-B cells). Both Br-mCD4s and Br-MΦs harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-MΦs. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain. IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4+ T cells harbor replication-competent SIV DNA; however, only brain CD4+ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.Cheri A. LeeErin BeasleyKarthikeyan SundarMargery SmelkinsonCarol VintonClaire DeleageKenta MatsudaFan WuJake D. EstesBernard A. P. LafontJason M. BrenchleyVanessa M. HirschAmerican Society for MicrobiologyarticleAIDSCD4 T cellscentral nervous system infectionsencephalitisinflammationmacrophagesMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	AIDS CD4 T cells central nervous system infections encephalitis inflammation macrophages Microbiology QR1-502
spellingShingle	AIDS CD4 T cells central nervous system infections encephalitis inflammation macrophages Microbiology QR1-502 Cheri A. Lee Erin Beasley Karthikeyan Sundar Margery Smelkinson Carol Vinton Claire Deleage Kenta Matsuda Fan Wu Jake D. Estes Bernard A. P. Lafont Jason M. Brenchley Vanessa M. Hirsch Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS
description	ABSTRACT Simian immunodeficiency virus (SIV)-infected nonhuman primates can serve as a relevant model for AIDS neuropathogenesis. Current SIV-induced encephalitis (SIVE)/neurological complications of AIDS (neuroAIDS) models are generally associated with rapid progression to neuroAIDS, which does not reflect the tempo of neuroAIDS progression in humans. Recently, we isolated a neuropathogenic clone, SIVsm804E-CL757 (CL757), obtained from an SIV-infected rhesus macaque (RM). CL757 causes a more protracted progression to disease, inducing SIVE in 50% of inoculated animals, with high cerebral spinal fluid viral loads, multinucleated giant cells (MNGCs), and perivascular lymphocytic cuffing in the central nervous system (CNS). This latter finding is reminiscent of human immunodeficiency virus (HIV) encephalitis in humans but not generally observed in rapid progressor animals with neuroAIDS. Here, we studied which subsets of cells within the CNS were targeted by CL757 in animals with neurological symptoms of SIVE. Immunohistochemistry of brain sections demonstrated infiltration of CD4+ T cells (CD4) and macrophages (MΦs) to the site of MNGCs. Moreover, an increase in mononuclear cells isolated from the brain tissues of RMs with SIVE correlated with increased cerebrospinal fluid (CSF) viral load. Subset analysis showed a specific increase in brain CD4+ memory T cells (Br-mCD4), brain-MΦs (Br-MΦs), and brain B cells (Br-B cells). Both Br-mCD4s and Br-MΦs harbored replication-competent viral DNA, as demonstrated by virus isolation by coculture. However, only in animals exhibiting SIVE/neuroAIDS was virus isolated from Br-MΦs. These findings support the use of CL757 to study the pathogenesis of AIDS viruses in the central nervous system and indicate a previously unanticipated role of CD4s cells as a potential reservoir in the brain. IMPORTANCE While the use of combination antiretroviral therapy effectively suppresses systemic viral replication in the body, neurocognitive disorders as a result of HIV infection of the central nervous system (CNS) remain a clinical problem. Therefore, the use of nonhuman primate models is necessary to study mechanisms of neuropathogenesis. The neurotropic, molecular clone SIVsm804E-CL757 (CL757) results in neuroAIDS in 50% of infected rhesus macaques approximately 1 year postinfection. Using CL757-infected macaques, we investigate disease progression by examining subsets of cells within the CNS that were targeted by CL757 and could potentially serve as viral reservoirs. By isolating mononuclear cells from the brains of SIV-infected rhesus macaques with and without encephalitis, we show that immune cells invade the neuroparenchyma and increase in number in the CNS in animals with SIV-induced encephalitis (SIVE). Of these cells, both brain macrophages and brain memory CD4+ T cells harbor replication-competent SIV DNA; however, only brain CD4+ T cells harbored SIV DNA in animals without SIVE. These findings support use of CL757 as an important model to investigate disease progression in the CNS and as a model to study virus reservoirs in the CNS.
format	article
author	Cheri A. Lee Erin Beasley Karthikeyan Sundar Margery Smelkinson Carol Vinton Claire Deleage Kenta Matsuda Fan Wu Jake D. Estes Bernard A. P. Lafont Jason M. Brenchley Vanessa M. Hirsch
author_facet	Cheri A. Lee Erin Beasley Karthikeyan Sundar Margery Smelkinson Carol Vinton Claire Deleage Kenta Matsuda Fan Wu Jake D. Estes Bernard A. P. Lafont Jason M. Brenchley Vanessa M. Hirsch
author_sort	Cheri A. Lee
title	Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS
title_short	Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS
title_full	Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS
title_fullStr	Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS
title_full_unstemmed	Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS
title_sort	simian immunodeficiency virus-infected memory cd4<sup>+</sup> t cells infiltrate to the site of infected macrophages in the neuroparenchyma of a chronic macaque model of neurological complications of aids
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/40f2856af6be4f2a8fb0aa9a0ec10809
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Simian Immunodeficiency Virus-Infected Memory CD4<sup>+</sup> T Cells Infiltrate to the Site of Infected Macrophages in the Neuroparenchyma of a Chronic Macaque Model of Neurological Complications of AIDS

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