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A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1
BACKGROUND: HIV-1 infection remains a major public health concern despite effective combination antiretroviral therapy (cART). The virus enters the central nervous system (CNS) early in infection and continues to cause HIV-associated neurocognitive disorders (HAND). The pathogenic mechanisms of HIV-...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388458/ https://www.ncbi.nlm.nih.gov/pubmed/32727588 http://dx.doi.org/10.1186/s12974-020-01894-2 |
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author | Singh, Hina Ojeda-Juárez, Daniel Maung, Ricky Shah, Rohan Roberts, Amanda J. Kaul, Marcus |
author_facet | Singh, Hina Ojeda-Juárez, Daniel Maung, Ricky Shah, Rohan Roberts, Amanda J. Kaul, Marcus |
author_sort | Singh, Hina |
collection | PubMed |
description | BACKGROUND: HIV-1 infection remains a major public health concern despite effective combination antiretroviral therapy (cART). The virus enters the central nervous system (CNS) early in infection and continues to cause HIV-associated neurocognitive disorders (HAND). The pathogenic mechanisms of HIV-associated brain injury remain incompletely understood. Since HIV-1 activates the type I interferon system, which signals via interferon-α receptor (IFNAR) 1 and 2, this study investigated the potential role of IFNAR1 in HIV-induced neurotoxicity. METHODS: We cross-bred HIVgp120-transgenic (tg) and IFNAR1 knockout (IFNAR1KO) mice. At 11–14 months of age, we performed a behavioral assessment and subsequently analyzed neuropathological alterations using deconvolution and quantitative immunofluorescence microscopy, quantitative RT-PCR, and bioinformatics. Western blotting of brain lysates and an in vitro neurotoxicity assay were employed for analysis of cellular signaling pathways. RESULTS: We show that IFNAR1KO results in partial, sex-dependent protection from neuronal injury and behavioral deficits in a transgenic model of HIV-induced brain injury. The IFNAR1KO rescues spatial memory and ameliorates loss of presynaptic terminals preferentially in female HIVgp120tg mice. Similarly, expression of genes involved in neurotransmission reveals sex-dependent effects of IFNAR1KO and HIVgp120. In contrast, IFNAR1-deficiency, independent of sex, limits damage to neuronal dendrites, microgliosis, and activation of p38 MAPK and restores ERK activity in the HIVgp120tg brain. In vitro, inhibition of p38 MAPK abrogates neurotoxicity caused similarly by blockade of ERK kinase and HIVgp120. CONCLUSION: Our findings indicate that IFNAR1 plays a pivotal role in both sex-dependent and independent processes of neuronal injury and behavioral impairment triggered by HIV-1. |
format | Online Article Text |
id | pubmed-7388458 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-73884582020-07-31 A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1 Singh, Hina Ojeda-Juárez, Daniel Maung, Ricky Shah, Rohan Roberts, Amanda J. Kaul, Marcus J Neuroinflammation Research BACKGROUND: HIV-1 infection remains a major public health concern despite effective combination antiretroviral therapy (cART). The virus enters the central nervous system (CNS) early in infection and continues to cause HIV-associated neurocognitive disorders (HAND). The pathogenic mechanisms of HIV-associated brain injury remain incompletely understood. Since HIV-1 activates the type I interferon system, which signals via interferon-α receptor (IFNAR) 1 and 2, this study investigated the potential role of IFNAR1 in HIV-induced neurotoxicity. METHODS: We cross-bred HIVgp120-transgenic (tg) and IFNAR1 knockout (IFNAR1KO) mice. At 11–14 months of age, we performed a behavioral assessment and subsequently analyzed neuropathological alterations using deconvolution and quantitative immunofluorescence microscopy, quantitative RT-PCR, and bioinformatics. Western blotting of brain lysates and an in vitro neurotoxicity assay were employed for analysis of cellular signaling pathways. RESULTS: We show that IFNAR1KO results in partial, sex-dependent protection from neuronal injury and behavioral deficits in a transgenic model of HIV-induced brain injury. The IFNAR1KO rescues spatial memory and ameliorates loss of presynaptic terminals preferentially in female HIVgp120tg mice. Similarly, expression of genes involved in neurotransmission reveals sex-dependent effects of IFNAR1KO and HIVgp120. In contrast, IFNAR1-deficiency, independent of sex, limits damage to neuronal dendrites, microgliosis, and activation of p38 MAPK and restores ERK activity in the HIVgp120tg brain. In vitro, inhibition of p38 MAPK abrogates neurotoxicity caused similarly by blockade of ERK kinase and HIVgp120. CONCLUSION: Our findings indicate that IFNAR1 plays a pivotal role in both sex-dependent and independent processes of neuronal injury and behavioral impairment triggered by HIV-1. BioMed Central 2020-07-29 /pmc/articles/PMC7388458/ /pubmed/32727588 http://dx.doi.org/10.1186/s12974-020-01894-2 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Singh, Hina Ojeda-Juárez, Daniel Maung, Ricky Shah, Rohan Roberts, Amanda J. Kaul, Marcus A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1 |
title | A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1 |
title_full | A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1 |
title_fullStr | A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1 |
title_full_unstemmed | A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1 |
title_short | A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1 |
title_sort | pivotal role for interferon-α receptor-1 in neuronal injury induced by hiv-1 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388458/ https://www.ncbi.nlm.nih.gov/pubmed/32727588 http://dx.doi.org/10.1186/s12974-020-01894-2 |
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