SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection
Abstract Understanding the neurobiological mechanisms underlying HIV-associated neurocognitive decline in people living with HIV is frequently complicated by an inability to analyze changes across the course of the infection and frequent presence of comorbid psychiatric and substance use disorders....
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Nature Publishing Group
2025-01-01
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| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-025-03261-2 |
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| author | Richard C. Crist Samar N. Chehimi Saurabh S. Divakaran Michael J. Montague Sébastien Tremblay Noah Snyder-Mackler Martin O. Bohlen Kenneth L. Chiou Trish M. Zintel Cayo Biobank Research Unit Michael L. Platt Halvor Juul Guido Silvestri Matthew R. Hayes Dennis L. Kolson Benjamin C. Reiner |
| author_facet | Richard C. Crist Samar N. Chehimi Saurabh S. Divakaran Michael J. Montague Sébastien Tremblay Noah Snyder-Mackler Martin O. Bohlen Kenneth L. Chiou Trish M. Zintel Cayo Biobank Research Unit Michael L. Platt Halvor Juul Guido Silvestri Matthew R. Hayes Dennis L. Kolson Benjamin C. Reiner |
| author_sort | Richard C. Crist |
| collection | DOAJ |
| description | Abstract Understanding the neurobiological mechanisms underlying HIV-associated neurocognitive decline in people living with HIV is frequently complicated by an inability to analyze changes across the course of the infection and frequent presence of comorbid psychiatric and substance use disorders. Preclinical non-human primate simian immunodeficiency virus (SIV) models help address these shortcomings. However, SIV studies frequently target protracted endpoints, limiting our understanding of the neuromolecular alterations during the early post-infection window. To begin to address this knowledge gap, we utilized single nuclei transcriptomics to examine frontal cortex samples of rhesus macaques 10- and 20-days post-SIV infection, compared to non-infected controls. We identify and validated a decrease in inhibitory neurons during the early post infection window, representing a potential substrate of longer-term injury and neurocognitive impairment in people living with HIV. Differential expression identified alterations in cellular subtype gene expression that persisted over the 20-day time course and short-lived differences only detected at 10-days post-SIV infection. In silico predicted regulatory mechanisms and dysregulated neural signaling pathways are presented. Analysis of cell-cell interaction networks identify altered signal pathways in the frontal cortex that may represent regional alterations in cell-cell communications. In total, these results identify cell type-specific molecular mechanisms putatively capable of underlying long-term neurocognitive alterations in persons living with HIV. |
| format | Article |
| id | doaj-art-83bc9c897102424ebac276077e433d56 |
| institution | Kabale University |
| issn | 2158-3188 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj-art-83bc9c897102424ebac276077e433d562025-02-02T12:43:32ZengNature Publishing GroupTranslational Psychiatry2158-31882025-01-0115111210.1038/s41398-025-03261-2SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infectionRichard C. Crist0Samar N. Chehimi1Saurabh S. Divakaran2Michael J. Montague3Sébastien Tremblay4Noah Snyder-Mackler5Martin O. Bohlen6Kenneth L. Chiou7Trish M. Zintel8Cayo Biobank Research UnitMichael L. Platt9Halvor Juul10Guido Silvestri11Matthew R. Hayes12Dennis L. Kolson13Benjamin C. Reiner14Department of Psychiatry, Perelman School of Medicine, University of PennsylvaniaDepartment of Psychiatry, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Neuroscience, University of PennsylvaniaDepartment of Neuroscience, University of PennsylvaniaCenter for Evolution and Medicine, Arizona State UniversityDepartment of Biomedical Engineering, Duke UniversityCenter for Evolution and Medicine, Arizona State UniversityCenter for Evolution and Medicine, Arizona State UniversityDepartment of Neuroscience, University of PennsylvaniaDepartment of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Medicine, Division of Infectious Diseases, Emory University School of MedicineDepartment of Psychiatry, Perelman School of Medicine, University of PennsylvaniaDepartment of Neurology, Perelman School of Medicine, University of PennsylvaniaDepartment of Psychiatry, Perelman School of Medicine, University of PennsylvaniaAbstract Understanding the neurobiological mechanisms underlying HIV-associated neurocognitive decline in people living with HIV is frequently complicated by an inability to analyze changes across the course of the infection and frequent presence of comorbid psychiatric and substance use disorders. Preclinical non-human primate simian immunodeficiency virus (SIV) models help address these shortcomings. However, SIV studies frequently target protracted endpoints, limiting our understanding of the neuromolecular alterations during the early post-infection window. To begin to address this knowledge gap, we utilized single nuclei transcriptomics to examine frontal cortex samples of rhesus macaques 10- and 20-days post-SIV infection, compared to non-infected controls. We identify and validated a decrease in inhibitory neurons during the early post infection window, representing a potential substrate of longer-term injury and neurocognitive impairment in people living with HIV. Differential expression identified alterations in cellular subtype gene expression that persisted over the 20-day time course and short-lived differences only detected at 10-days post-SIV infection. In silico predicted regulatory mechanisms and dysregulated neural signaling pathways are presented. Analysis of cell-cell interaction networks identify altered signal pathways in the frontal cortex that may represent regional alterations in cell-cell communications. In total, these results identify cell type-specific molecular mechanisms putatively capable of underlying long-term neurocognitive alterations in persons living with HIV.https://doi.org/10.1038/s41398-025-03261-2 |
| spellingShingle | Richard C. Crist Samar N. Chehimi Saurabh S. Divakaran Michael J. Montague Sébastien Tremblay Noah Snyder-Mackler Martin O. Bohlen Kenneth L. Chiou Trish M. Zintel Cayo Biobank Research Unit Michael L. Platt Halvor Juul Guido Silvestri Matthew R. Hayes Dennis L. Kolson Benjamin C. Reiner SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection Translational Psychiatry |
| title | SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection |
| title_full | SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection |
| title_fullStr | SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection |
| title_full_unstemmed | SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection |
| title_short | SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection |
| title_sort | siv infection induces alterations in gene expression and loss of interneurons in rhesus macaque frontal cortex during early systemic infection |
| url | https://doi.org/10.1038/s41398-025-03261-2 |
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