Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

ABSTRACT The exact cause of neurocognitive dysfunction in HIV-positive patients despite successful control of the infection in the periphery is not completely understood. One suggested mechanism is a vicious cycle of microglial activation and release of proinflammatory chemokines/cytokines that even...

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Autores principales:	Dima A. Hammoud, Sanhita Sinharay, Swati Shah, William Schreiber-Stainthorp, Dragan Maric, Siva Muthusamy, Dianne E. Lee, Cheri A. Lee, Falguni Basuli, William C. Reid, Paul Wakim, Kenta Matsuda, Vanessa Hirsch, Avindra Nath, Michele Di Mascio
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	DPA714 SIV encephalitis neuroinflammation positron emission tomography rhesus macaques translocator protein Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ae132e61bc8c41d5aeae351172282a96
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spelling	oai:doaj.org-article:ae132e61bc8c41d5aeae351172282a962021-11-15T15:55:24ZNeuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis10.1128/mBio.00970-192150-7511https://doaj.org/article/ae132e61bc8c41d5aeae351172282a962019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00970-19https://doaj.org/toc/2150-7511ABSTRACT The exact cause of neurocognitive dysfunction in HIV-positive patients despite successful control of the infection in the periphery is not completely understood. One suggested mechanism is a vicious cycle of microglial activation and release of proinflammatory chemokines/cytokines that eventually leads to neuronal loss and dysfunction. However, the exact role of microglial activation in the earliest stages of the infection with high cerebrospinal fluid (CSF) viral loads (VL) is unclear. In this study, we imaged the translocator protein (TSPO), a mitochondrial membrane receptor known to be upregulated in activated microglia and macrophages, in rhesus macaques before and multiple times after inoculation with a neurotropic simian immunodeficiency virus (SIV) strain (SIVsm804E), using 18F-DPA714 positron emission tomography (PET). The whole-brain standardized uptake values of TSPO at equilibrium reflecting total binding (SUVT) and binding potentials (BPND) were calculated and correlated with CSF and serum markers of disease, and a corresponding postmortem immunostaining analysis was also performed. SUVT was found to be inversely correlated with both CSF VL and monocyte chemoattractant protein 1 (MCP-1) levels. In SIV-infected macaques with very high CSF VL at necropsy (>106 copies/ml), we found decreased TSPO binding by PET, and this was supported by immunostaining which showed glial and neuronal apoptosis rather than microglial activation. On the other hand, with only moderately elevated CSF VL (∼104 copies/ml), we found increased TSPO binding as well as focal and diffuse microglial activation on immunostaining. Our results in the SIV-infected macaque model provide insights into the relationship between HIV neuropathology and CSF VL at various stages of the disease. IMPORTANCE Neurological and cognitive problems are a common complication of HIV infection and are prevalent even in treated individuals. Although the molecular processes underlying brain involvement with HIV are not completely understood, inflammation is suspected to play a significant role. Our work presents an in vivo assessment of neuroinflammation in an animal model of HIV, the simian immunodeficiency virus (SIV)-infected rhesus macaque. Using positron emission tomography (PET) imaging, we identified changes in brain inflammation after inoculation with SIV over time. Interestingly, we found decreased binding of the PET ligand in the presence of very high cerebrospinal fluid (CSF) viral loads. These findings were supported by immunostaining which showed marked glial loss instead of inflammation. This study provides insight into glial and neuronal changes associated with very high CSF viral load and could reflect similar changes occurring in HIV-infected patients.Dima A. HammoudSanhita SinharaySwati ShahWilliam Schreiber-StainthorpDragan MaricSiva MuthusamyDianne E. LeeCheri A. LeeFalguni BasuliWilliam C. ReidPaul WakimKenta MatsudaVanessa HirschAvindra NathMichele Di MascioAmerican Society for MicrobiologyarticleDPA714SIV encephalitisneuroinflammationpositron emission tomographyrhesus macaquestranslocator proteinMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	DPA714 SIV encephalitis neuroinflammation positron emission tomography rhesus macaques translocator protein Microbiology QR1-502
spellingShingle	DPA714 SIV encephalitis neuroinflammation positron emission tomography rhesus macaques translocator protein Microbiology QR1-502 Dima A. Hammoud Sanhita Sinharay Swati Shah William Schreiber-Stainthorp Dragan Maric Siva Muthusamy Dianne E. Lee Cheri A. Lee Falguni Basuli William C. Reid Paul Wakim Kenta Matsuda Vanessa Hirsch Avindra Nath Michele Di Mascio Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis
description	ABSTRACT The exact cause of neurocognitive dysfunction in HIV-positive patients despite successful control of the infection in the periphery is not completely understood. One suggested mechanism is a vicious cycle of microglial activation and release of proinflammatory chemokines/cytokines that eventually leads to neuronal loss and dysfunction. However, the exact role of microglial activation in the earliest stages of the infection with high cerebrospinal fluid (CSF) viral loads (VL) is unclear. In this study, we imaged the translocator protein (TSPO), a mitochondrial membrane receptor known to be upregulated in activated microglia and macrophages, in rhesus macaques before and multiple times after inoculation with a neurotropic simian immunodeficiency virus (SIV) strain (SIVsm804E), using 18F-DPA714 positron emission tomography (PET). The whole-brain standardized uptake values of TSPO at equilibrium reflecting total binding (SUVT) and binding potentials (BPND) were calculated and correlated with CSF and serum markers of disease, and a corresponding postmortem immunostaining analysis was also performed. SUVT was found to be inversely correlated with both CSF VL and monocyte chemoattractant protein 1 (MCP-1) levels. In SIV-infected macaques with very high CSF VL at necropsy (>106 copies/ml), we found decreased TSPO binding by PET, and this was supported by immunostaining which showed glial and neuronal apoptosis rather than microglial activation. On the other hand, with only moderately elevated CSF VL (∼104 copies/ml), we found increased TSPO binding as well as focal and diffuse microglial activation on immunostaining. Our results in the SIV-infected macaque model provide insights into the relationship between HIV neuropathology and CSF VL at various stages of the disease. IMPORTANCE Neurological and cognitive problems are a common complication of HIV infection and are prevalent even in treated individuals. Although the molecular processes underlying brain involvement with HIV are not completely understood, inflammation is suspected to play a significant role. Our work presents an in vivo assessment of neuroinflammation in an animal model of HIV, the simian immunodeficiency virus (SIV)-infected rhesus macaque. Using positron emission tomography (PET) imaging, we identified changes in brain inflammation after inoculation with SIV over time. Interestingly, we found decreased binding of the PET ligand in the presence of very high cerebrospinal fluid (CSF) viral loads. These findings were supported by immunostaining which showed marked glial loss instead of inflammation. This study provides insight into glial and neuronal changes associated with very high CSF viral load and could reflect similar changes occurring in HIV-infected patients.
format	article
author	Dima A. Hammoud Sanhita Sinharay Swati Shah William Schreiber-Stainthorp Dragan Maric Siva Muthusamy Dianne E. Lee Cheri A. Lee Falguni Basuli William C. Reid Paul Wakim Kenta Matsuda Vanessa Hirsch Avindra Nath Michele Di Mascio
author_facet	Dima A. Hammoud Sanhita Sinharay Swati Shah William Schreiber-Stainthorp Dragan Maric Siva Muthusamy Dianne E. Lee Cheri A. Lee Falguni Basuli William C. Reid Paul Wakim Kenta Matsuda Vanessa Hirsch Avindra Nath Michele Di Mascio
author_sort	Dima A. Hammoud
title	Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis
title_short	Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis
title_full	Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis
title_fullStr	Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis
title_full_unstemmed	Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis
title_sort	neuroinflammatory changes in relation to cerebrospinal fluid viral load in simian immunodeficiency virus encephalitis
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/ae132e61bc8c41d5aeae351172282a96
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Neuroinflammatory Changes in Relation to Cerebrospinal Fluid Viral Load in Simian Immunodeficiency Virus Encephalitis

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