Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir
ABSTRACT A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2017-09-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mBio.01186-17 |
| _version_ | 1818843705817169920 |
|---|---|
| author | Claudia R. Avalos Celina M. Abreu Suzanne E. Queen Ming Li Sarah Price Erin N. Shirk Elizabeth L. Engle Ellen Forsyth Brandon T. Bullock Feilim Mac Gabhann Stephen W. Wietgrefe Ashley T. Haase M. Christine Zink Joseph L. Mankowski Janice E. Clements Lucio Gama |
| author_facet | Claudia R. Avalos Celina M. Abreu Suzanne E. Queen Ming Li Sarah Price Erin N. Shirk Elizabeth L. Engle Ellen Forsyth Brandon T. Bullock Feilim Mac Gabhann Stephen W. Wietgrefe Ashley T. Haase M. Christine Zink Joseph L. Mankowski Janice E. Clements Lucio Gama |
| author_sort | Claudia R. Avalos |
| collection | DOAJ |
| description | ABSTRACT A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. IMPORTANCE Resting CD4+ T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4+ T cells and underscore the importance of macrophages in developing strategies to eradicate HIV. |
| first_indexed | 2024-12-19T05:02:07Z |
| format | Article |
| id | doaj.art-cc2e12c107704e4d86a6f1bc8f4383ea |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-19T05:02:07Z |
| publishDate | 2017-09-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-cc2e12c107704e4d86a6f1bc8f4383ea2022-12-21T20:35:02ZengAmerican Society for MicrobiologymBio2150-75112017-09-018410.1128/mBio.01186-17Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent ReservoirClaudia R. Avalos0Celina M. Abreu1Suzanne E. Queen2Ming Li3Sarah Price4Erin N. Shirk5Elizabeth L. Engle6Ellen Forsyth7Brandon T. Bullock8Feilim Mac Gabhann9Stephen W. Wietgrefe10Ashley T. Haase11M. Christine Zink12Joseph L. Mankowski13Janice E. Clements14Lucio Gama15Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, USADepartment of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USADepartment of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, Minnesota, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USADepartment of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, Maryland, USAABSTRACT A human immunodeficiency virus (HIV) infection cure requires an understanding of the cellular and anatomical sites harboring virus that contribute to viral rebound upon treatment interruption. Despite antiretroviral therapy (ART), HIV-associated neurocognitive disorders (HAND) are reported in HIV-infected individuals on ART. Biomarkers for macrophage activation and neuronal damage in cerebrospinal fluid (CSF) of HIV-infected individuals demonstrate continued effects of HIV in brain and suggest that the central nervous system (CNS) may serve as a viral reservoir. Using a simian immunodeficiency virus (SIV)/macaque model for HIV encephalitis and AIDS, we evaluated whether infected cells persist in brain despite ART. Eight SIV-infected pig-tailed macaques were virally suppressed with ART, and plasma and CSF viremia levels were analyzed longitudinally. To assess whether virus persisted in brain macrophages (BrMΦ) in these macaques, we used a macrophage quantitative viral outgrowth assay (MΦ-QVOA), PCR, and in situ hybridization (ISH) to measure the frequency of infected cells and the levels of viral RNA and DNA in brain. Viral RNA in brain tissue of suppressed macaques was undetectable, although viral DNA was detected in all animals. The MΦ-QVOA demonstrated that the majority of suppressed animals contained latently infected BrMΦ. We also showed that virus produced in the MΦ-QVOAs was replication competent, suggesting that latently infected BrMΦ are capable of reestablishing productive infection upon treatment interruption. This report provides the first confirmation of the presence of replication-competent SIV in BrMΦ of ART-suppressed macaques and suggests that the highly debated issue of viral latency in macrophages, at least in brain, has been addressed in SIV-infected macaques treated with ART. IMPORTANCE Resting CD4+ T cells are currently the only cells that fit the definition of a latent reservoir. However, recent evidence suggests that HIV/SIV-infected macrophages persist despite ART. Markers of macrophage activation and neuronal damage are observed in the CSF of HIV-infected individuals and of SIV-infected macaques on suppressive ART regimens, suggesting that the CNS has continued virus infection and latent infection. A controversy exists as to whether brain macrophages represent a latent source of replication-competent virus capable of reestablishing infection upon treatment interruption. In this study, we demonstrated the presence of the latent macrophage reservoir in brains of SIV-infected ART-treated macaques and analyzed the reservoir using our established outgrowth assay to quantitate macrophages harboring replication-competent SIV genomes. Our results support the idea of the existence of other latent reservoirs in addition to resting CD4+ T cells and underscore the importance of macrophages in developing strategies to eradicate HIV.https://journals.asm.org/doi/10.1128/mBio.01186-17brainhuman immunodeficiency viruslatencymacrophagessimian immunodeficiency virus |
| spellingShingle | Claudia R. Avalos Celina M. Abreu Suzanne E. Queen Ming Li Sarah Price Erin N. Shirk Elizabeth L. Engle Ellen Forsyth Brandon T. Bullock Feilim Mac Gabhann Stephen W. Wietgrefe Ashley T. Haase M. Christine Zink Joseph L. Mankowski Janice E. Clements Lucio Gama Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir mBio brain human immunodeficiency virus latency macrophages simian immunodeficiency virus |
| title | Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir |
| title_full | Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir |
| title_fullStr | Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir |
| title_full_unstemmed | Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir |
| title_short | Brain Macrophages in Simian Immunodeficiency Virus-Infected, Antiretroviral-Suppressed Macaques: a Functional Latent Reservoir |
| title_sort | brain macrophages in simian immunodeficiency virus infected antiretroviral suppressed macaques a functional latent reservoir |
| topic | brain human immunodeficiency virus latency macrophages simian immunodeficiency virus |
| url | https://journals.asm.org/doi/10.1128/mBio.01186-17 |
| work_keys_str_mv | AT claudiaravalos brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT celinamabreu brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT suzanneequeen brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT mingli brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT sarahprice brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT erinnshirk brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT elizabethlengle brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT ellenforsyth brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT brandontbullock brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT feilimmacgabhann brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT stephenwwietgrefe brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT ashleythaase brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT mchristinezink brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT josephlmankowski brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT janiceeclements brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir AT luciogama brainmacrophagesinsimianimmunodeficiencyvirusinfectedantiretroviralsuppressedmacaquesafunctionallatentreservoir |