Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment

ABSTRACT HIV causes neurodegeneration and dementia in AIDS patients, but its function in milder cognitive impairments in virologically suppressed patients on antiretroviral therapy is unknown. Such patients are immunocompetent, have low peripheral and brain HIV burdens, and show minimal brain neurop...

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Autores principales:	Jennifer Kelschenbach, Hongxia He, Boe-Hyun Kim, Alejandra Borjabad, Chao-Jiang Gu, Wei Chao, Meilan Do, Leroy R. Sharer, Hong Zhang, Ottavio Arancio, Mary Jane Potash, David J. Volsky
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	EcoHIV HAND mouse models radial arm water maze synaptodendritic injury Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/647ff4c2424c40439623f7e83ef035e1
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spelling	oai:doaj.org-article:647ff4c2424c40439623f7e83ef035e12021-11-15T16:22:08ZEfficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment10.1128/mBio.00591-192150-7511https://doaj.org/article/647ff4c2424c40439623f7e83ef035e12019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00591-19https://doaj.org/toc/2150-7511ABSTRACT HIV causes neurodegeneration and dementia in AIDS patients, but its function in milder cognitive impairments in virologically suppressed patients on antiretroviral therapy is unknown. Such patients are immunocompetent, have low peripheral and brain HIV burdens, and show minimal brain neuropathology. Using the model of HIV-related memory impairment in EcoHIV-infected conventional mice, we investigated the neurobiological and cognitive consequences of efficient EcoHIV expression in the mouse brain after intracerebral infection. HIV integrated and persisted in an expressed state in brain tissue, was detectable in brain monocytic cells, and caused neuroinflammatory responses and lasting spatial, working, and associative memory impairment. Systemic antiretroviral treatment prevented direct brain infection and memory dysfunction indicating the requirement for HIV expression in the brain for disease. Similarly inoculated murine leukemia virus used as a control replicated in mouse brain but not in monocytic cells and was cognitively benign, linking the disease to HIV-specific functions. Memory impairment correlated in real time with hippocampal dysfunction shown by defective long-term potentiation in hippocampal slices ex vivo and with diffuse synaptodendritic injury in the hippocampus reflected in significant reduction in microtubule-associated protein 2 and synapsin II staining. In contrast, there was no evidence of overt neuronal loss in this region as determined by neuron-specific nuclear protein quantification, TUNEL assay, and histological observations. Our results reveal a novel capacity of HIV to induce neuronal dysfunction and memory impairment independent of neurotoxicity, distinct from the neurotoxicity of HIV infection in dementia. IMPORTANCE HIV neuropathogenesis has been attributed in large measure to neurotoxicity of viral proteins and inflammatory factors produced by infected monocytic cells in the brain. We show here that HIV expression in mouse brain causes lasting memory impairment by a mechanism involving injury to hippocampal synaptodendritic arbors and neuronal function but not overt neuronal loss in the region. Our results mirror the observation of minimal neurodegeneration in cognitively impaired HIV patients on antiretroviral therapy and demonstrate that HIV is nonneurotoxic in certain brain abnormalities that it causes. If neurons comprising the cognition-related networks survive HIV insult, at least for some time, there is a window of opportunity for disease treatment.Jennifer KelschenbachHongxia HeBoe-Hyun KimAlejandra BorjabadChao-Jiang GuWei ChaoMeilan DoLeroy R. SharerHong ZhangOttavio ArancioMary Jane PotashDavid J. VolskyAmerican Society for MicrobiologyarticleEcoHIVHANDmouse modelsradial arm water mazesynaptodendritic injuryMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	EcoHIV HAND mouse models radial arm water maze synaptodendritic injury Microbiology QR1-502
spellingShingle	EcoHIV HAND mouse models radial arm water maze synaptodendritic injury Microbiology QR1-502 Jennifer Kelschenbach Hongxia He Boe-Hyun Kim Alejandra Borjabad Chao-Jiang Gu Wei Chao Meilan Do Leroy R. Sharer Hong Zhang Ottavio Arancio Mary Jane Potash David J. Volsky Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment
description	ABSTRACT HIV causes neurodegeneration and dementia in AIDS patients, but its function in milder cognitive impairments in virologically suppressed patients on antiretroviral therapy is unknown. Such patients are immunocompetent, have low peripheral and brain HIV burdens, and show minimal brain neuropathology. Using the model of HIV-related memory impairment in EcoHIV-infected conventional mice, we investigated the neurobiological and cognitive consequences of efficient EcoHIV expression in the mouse brain after intracerebral infection. HIV integrated and persisted in an expressed state in brain tissue, was detectable in brain monocytic cells, and caused neuroinflammatory responses and lasting spatial, working, and associative memory impairment. Systemic antiretroviral treatment prevented direct brain infection and memory dysfunction indicating the requirement for HIV expression in the brain for disease. Similarly inoculated murine leukemia virus used as a control replicated in mouse brain but not in monocytic cells and was cognitively benign, linking the disease to HIV-specific functions. Memory impairment correlated in real time with hippocampal dysfunction shown by defective long-term potentiation in hippocampal slices ex vivo and with diffuse synaptodendritic injury in the hippocampus reflected in significant reduction in microtubule-associated protein 2 and synapsin II staining. In contrast, there was no evidence of overt neuronal loss in this region as determined by neuron-specific nuclear protein quantification, TUNEL assay, and histological observations. Our results reveal a novel capacity of HIV to induce neuronal dysfunction and memory impairment independent of neurotoxicity, distinct from the neurotoxicity of HIV infection in dementia. IMPORTANCE HIV neuropathogenesis has been attributed in large measure to neurotoxicity of viral proteins and inflammatory factors produced by infected monocytic cells in the brain. We show here that HIV expression in mouse brain causes lasting memory impairment by a mechanism involving injury to hippocampal synaptodendritic arbors and neuronal function but not overt neuronal loss in the region. Our results mirror the observation of minimal neurodegeneration in cognitively impaired HIV patients on antiretroviral therapy and demonstrate that HIV is nonneurotoxic in certain brain abnormalities that it causes. If neurons comprising the cognition-related networks survive HIV insult, at least for some time, there is a window of opportunity for disease treatment.
format	article
author	Jennifer Kelschenbach Hongxia He Boe-Hyun Kim Alejandra Borjabad Chao-Jiang Gu Wei Chao Meilan Do Leroy R. Sharer Hong Zhang Ottavio Arancio Mary Jane Potash David J. Volsky
author_facet	Jennifer Kelschenbach Hongxia He Boe-Hyun Kim Alejandra Borjabad Chao-Jiang Gu Wei Chao Meilan Do Leroy R. Sharer Hong Zhang Ottavio Arancio Mary Jane Potash David J. Volsky
author_sort	Jennifer Kelschenbach
title	Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment
title_short	Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment
title_full	Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment
title_fullStr	Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment
title_full_unstemmed	Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment
title_sort	efficient expression of hiv in immunocompetent mouse brain reveals a novel nonneurotoxic viral function in hippocampal synaptodendritic injury and memory impairment
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/647ff4c2424c40439623f7e83ef035e1
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Efficient Expression of HIV in Immunocompetent Mouse Brain Reveals a Novel Nonneurotoxic Viral Function in Hippocampal Synaptodendritic Injury and Memory Impairment

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