Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models
HIV remains incurable because of viral persistence in latent reservoirs that are inaccessible to antiretroviral therapy. A potential curative strategy is to reactivate viral gene expression in latently infected cells. However, no drug so far has proven to be successful in vivo in reducing the reserv...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253119301696 |
| _version_ | 1818416224912015360 |
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| author | María Rosa López-Huertas Matías Morín Nadia Madrid-Elena Carolina Gutiérrez Laura Jiménez-Tormo Javier Santoyo Francisco Sanz-Rodríguez Miguel Ángel Moreno Pelayo Laura García Bermejo Santiago Moreno |
| author_facet | María Rosa López-Huertas Matías Morín Nadia Madrid-Elena Carolina Gutiérrez Laura Jiménez-Tormo Javier Santoyo Francisco Sanz-Rodríguez Miguel Ángel Moreno Pelayo Laura García Bermejo Santiago Moreno |
| author_sort | María Rosa López-Huertas |
| collection | DOAJ |
| description | HIV remains incurable because of viral persistence in latent reservoirs that are inaccessible to antiretroviral therapy. A potential curative strategy is to reactivate viral gene expression in latently infected cells. However, no drug so far has proven to be successful in vivo in reducing the reservoir, and therefore new anti-latency compounds are needed. We explored the role of microRNAs (miRNAs) in latency maintenance and their modulation as a potential anti-latency strategy. Latency models based on treating resting CD4 T cells with chemokine (C-C motif) ligand 19 (CCL19) or interleukin-7 (IL7) before HIV infection and next-generation sequencing were used to identify the miRNAs involved in HIV latency. We detected four upregulated miRNAs (miRNA-98, miRNA-4516, miRNA-4488, and miRNA-7974). Individual or combined inhibition of these miRNAs was performed by transfection into cells latently infected with HIV. Viral replication, assessed 72 h after transfection, did not increase after miRNA modulation, despite miRNA inhibition and lack of toxicity. Furthermore, the combined modulation of five miRNAs previously associated with HIV latency was not effective in these models. Our results do not support the modulation of miRNAs as a useful strategy for the reversal of HIV latency. As shown with other drugs, the potential of miRNA modulation as an HIV reactivation strategy could be dependent on the latency model used. Keywords: HIV latency, latency-reversing agent, LRA, HIV latency model, CCL19, IL-7, miRNA modulation |
| first_indexed | 2024-12-14T11:47:30Z |
| format | Article |
| id | doaj.art-e4eef784a2814956b150029ec0a01d71 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-14T11:47:30Z |
| publishDate | 2019-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-e4eef784a2814956b150029ec0a01d712022-12-21T23:02:32ZengElsevierMolecular Therapy: Nucleic Acids2162-25312019-09-0117323336Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency ModelsMaría Rosa López-Huertas0Matías Morín1Nadia Madrid-Elena2Carolina Gutiérrez3Laura Jiménez-Tormo4Javier Santoyo5Francisco Sanz-Rodríguez6Miguel Ángel Moreno Pelayo7Laura García Bermejo8Santiago Moreno9Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; Corresponding author: Maria Rosa López-Huertas, PhD, Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, Carretera de Colmenar, Km 9.100, 28034 Madrid, Spain.Servicio de Genética, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, CIBERER, 28034 Madrid, SpainServicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, SpainServicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, SpainServicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, SpainEdinburgh Genomics, The Roslin Institute, University of Edinburgh, Scotland, UKFluorescence Imaging Group, Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, SpainServicio de Genética, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, CIBERER, 28034 Madrid, SpainGrupo de Biomarcadores y Dianas Terapéuticas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; Corresponding author: Laura García Bermejo, PhD, Grupo de Biomarcadores y Dianas Terapéuticas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, Hospital Universitario Ramón y Cajal, Carretera de Colmenar, Km 9.100, 28034 Madrid, Spain.Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá de Henares, 28871 Alcalá de Henares, SpainHIV remains incurable because of viral persistence in latent reservoirs that are inaccessible to antiretroviral therapy. A potential curative strategy is to reactivate viral gene expression in latently infected cells. However, no drug so far has proven to be successful in vivo in reducing the reservoir, and therefore new anti-latency compounds are needed. We explored the role of microRNAs (miRNAs) in latency maintenance and their modulation as a potential anti-latency strategy. Latency models based on treating resting CD4 T cells with chemokine (C-C motif) ligand 19 (CCL19) or interleukin-7 (IL7) before HIV infection and next-generation sequencing were used to identify the miRNAs involved in HIV latency. We detected four upregulated miRNAs (miRNA-98, miRNA-4516, miRNA-4488, and miRNA-7974). Individual or combined inhibition of these miRNAs was performed by transfection into cells latently infected with HIV. Viral replication, assessed 72 h after transfection, did not increase after miRNA modulation, despite miRNA inhibition and lack of toxicity. Furthermore, the combined modulation of five miRNAs previously associated with HIV latency was not effective in these models. Our results do not support the modulation of miRNAs as a useful strategy for the reversal of HIV latency. As shown with other drugs, the potential of miRNA modulation as an HIV reactivation strategy could be dependent on the latency model used. Keywords: HIV latency, latency-reversing agent, LRA, HIV latency model, CCL19, IL-7, miRNA modulationhttp://www.sciencedirect.com/science/article/pii/S2162253119301696 |
| spellingShingle | María Rosa López-Huertas Matías Morín Nadia Madrid-Elena Carolina Gutiérrez Laura Jiménez-Tormo Javier Santoyo Francisco Sanz-Rodríguez Miguel Ángel Moreno Pelayo Laura García Bermejo Santiago Moreno Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models Molecular Therapy: Nucleic Acids |
| title | Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models |
| title_full | Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models |
| title_fullStr | Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models |
| title_full_unstemmed | Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models |
| title_short | Selective miRNA Modulation Fails to Activate HIV Replication in In Vitro Latency Models |
| title_sort | selective mirna modulation fails to activate hiv replication in in vitro latency models |
| url | http://www.sciencedirect.com/science/article/pii/S2162253119301696 |
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