A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection
ABSTRACT Combined Antiretroviral therapy (cART) suppresses HIV replication but fails to eradicate the virus, which persists in a small pool of long-lived latently infected cells. Immune activation and residual inflammation during cART are considered to contribute to viral persistence. Galectins, a f...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-08-01
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| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.00611-22 |
| _version_ | 1797999779206135808 |
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| author | Julia Rubione Paula S. Pérez Alejandro Czernikier Gabriel A. Duette Federico Pehuen Pereyra Gerber Jimena Salido Martina P. Fabiano Yanina Ghiglione Gabriela Turk Natalia Laufer Alejandro J. Cagnoni Juan M. Pérez Sáez Joaquín P. Merlo Carla Pascuale Juan C. Stupirski Omar Sued Manuel Varas-Godoy Sharon R. Lewin Karina V. Mariño Gabriel A. Rabinovich Matías Ostrowski |
| author_facet | Julia Rubione Paula S. Pérez Alejandro Czernikier Gabriel A. Duette Federico Pehuen Pereyra Gerber Jimena Salido Martina P. Fabiano Yanina Ghiglione Gabriela Turk Natalia Laufer Alejandro J. Cagnoni Juan M. Pérez Sáez Joaquín P. Merlo Carla Pascuale Juan C. Stupirski Omar Sued Manuel Varas-Godoy Sharon R. Lewin Karina V. Mariño Gabriel A. Rabinovich Matías Ostrowski |
| author_sort | Julia Rubione |
| collection | DOAJ |
| description | ABSTRACT Combined Antiretroviral therapy (cART) suppresses HIV replication but fails to eradicate the virus, which persists in a small pool of long-lived latently infected cells. Immune activation and residual inflammation during cART are considered to contribute to viral persistence. Galectins, a family of β-galactoside-binding proteins, play central roles in host-pathogen interactions and inflammatory responses. Depending on their structure, glycan binding specificities and/or formation of distinct multivalent signaling complexes, different members of this family can complement, synergize, or oppose the function of others. Here, we identify a regulatory circuit, mediated by galectin-1 (Gal-1)–glycan interactions, that promotes reversal of HIV-1 latency in infected T cells. We found elevated levels of circulating Gal-1 in plasma from HIV-1-infected individuals, which correlated both with inflammatory markers and the transcriptional activity of the reservoir, as determined by unspliced-RNA (US-RNA) copy number. Proinflammatory extracellular vesicles (EVs) isolated from the plasma of HIV-infected individuals induced Gal-1 secretion by macrophages. Extracellularly, Gal-1 interacted with latently infected resting primary CD4+ T cells and J-LAT cells in a glycan-dependent manner and reversed HIV latency via activation of the nuclear factor κB (NF-κB). Furthermore, CD4+ T cells isolated from HIV-infected individuals showed increased HIV-1 transcriptional activity when exposed to Gal-1. Thus, by modulating reservoir dynamics, EV-driven Gal-1 secretion by macrophages links inflammation with HIV-1 persistence in cART-treated individuals. IMPORTANCE Antiretroviral therapy has led to a dramatic reduction in HIV-related morbidity and mortality. However, cART does not eradicate the virus, which persists in resting CD4+ T cells as the main viral reservoir, consequently requiring lifelong treatment. A major question is how the functional status of the immune system during antiretroviral therapy determines the activity and size of the viral reservoir. In this study, we identified a central role for galectin-1 (Gal-1), a glycan-binding protein released in response to extracellular vesicles (EVs), in modulating the activity of HIV reservoir, thus shaping chronic immune activation in HIV-infected patients. Our work unveils a central role of Gal-1 in linking chronic immune activation and reservoir dynamics, highlighting new therapeutic opportunities in HIV infection. |
| first_indexed | 2024-04-11T11:10:11Z |
| format | Article |
| id | doaj.art-e9d71457b2f84f5da38d7bf12b2e8d3e |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-04-11T11:10:11Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-e9d71457b2f84f5da38d7bf12b2e8d3e2022-12-22T04:27:58ZengAmerican Society for MicrobiologymBio2150-75112022-08-0113410.1128/mbio.00611-22A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 InfectionJulia Rubione0Paula S. Pérez1Alejandro Czernikier2Gabriel A. Duette3Federico Pehuen Pereyra Gerber4Jimena Salido5Martina P. Fabiano6Yanina Ghiglione7Gabriela Turk8Natalia Laufer9Alejandro J. Cagnoni10Juan M. Pérez Sáez11Joaquín P. Merlo12Carla Pascuale13Juan C. Stupirski14Omar Sued15Manuel Varas-Godoy16Sharon R. Lewin17Karina V. Mariño18Gabriel A. Rabinovich19Matías Ostrowski20Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaLaboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME—CONICET), Buenos Aires, ArgentinaLaboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME—CONICET), Buenos Aires, ArgentinaLaboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME—CONICET), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaLaboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME—CONICET), Buenos Aires, ArgentinaFundación Huésped, Buenos Aires, ArgentinaCancer Cell Biology Lab, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, ChileThe Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, AustraliaLaboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME—CONICET), Buenos Aires, ArgentinaLaboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME—CONICET), Buenos Aires, ArgentinaFacultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, ArgentinaABSTRACT Combined Antiretroviral therapy (cART) suppresses HIV replication but fails to eradicate the virus, which persists in a small pool of long-lived latently infected cells. Immune activation and residual inflammation during cART are considered to contribute to viral persistence. Galectins, a family of β-galactoside-binding proteins, play central roles in host-pathogen interactions and inflammatory responses. Depending on their structure, glycan binding specificities and/or formation of distinct multivalent signaling complexes, different members of this family can complement, synergize, or oppose the function of others. Here, we identify a regulatory circuit, mediated by galectin-1 (Gal-1)–glycan interactions, that promotes reversal of HIV-1 latency in infected T cells. We found elevated levels of circulating Gal-1 in plasma from HIV-1-infected individuals, which correlated both with inflammatory markers and the transcriptional activity of the reservoir, as determined by unspliced-RNA (US-RNA) copy number. Proinflammatory extracellular vesicles (EVs) isolated from the plasma of HIV-infected individuals induced Gal-1 secretion by macrophages. Extracellularly, Gal-1 interacted with latently infected resting primary CD4+ T cells and J-LAT cells in a glycan-dependent manner and reversed HIV latency via activation of the nuclear factor κB (NF-κB). Furthermore, CD4+ T cells isolated from HIV-infected individuals showed increased HIV-1 transcriptional activity when exposed to Gal-1. Thus, by modulating reservoir dynamics, EV-driven Gal-1 secretion by macrophages links inflammation with HIV-1 persistence in cART-treated individuals. IMPORTANCE Antiretroviral therapy has led to a dramatic reduction in HIV-related morbidity and mortality. However, cART does not eradicate the virus, which persists in resting CD4+ T cells as the main viral reservoir, consequently requiring lifelong treatment. A major question is how the functional status of the immune system during antiretroviral therapy determines the activity and size of the viral reservoir. In this study, we identified a central role for galectin-1 (Gal-1), a glycan-binding protein released in response to extracellular vesicles (EVs), in modulating the activity of HIV reservoir, thus shaping chronic immune activation in HIV-infected patients. Our work unveils a central role of Gal-1 in linking chronic immune activation and reservoir dynamics, highlighting new therapeutic opportunities in HIV infection.https://journals.asm.org/doi/10.1128/mbio.00611-22galectin-1human immunodeficiency virusextracellular vesiclesviral reservoirchronic inflammation |
| spellingShingle | Julia Rubione Paula S. Pérez Alejandro Czernikier Gabriel A. Duette Federico Pehuen Pereyra Gerber Jimena Salido Martina P. Fabiano Yanina Ghiglione Gabriela Turk Natalia Laufer Alejandro J. Cagnoni Juan M. Pérez Sáez Joaquín P. Merlo Carla Pascuale Juan C. Stupirski Omar Sued Manuel Varas-Godoy Sharon R. Lewin Karina V. Mariño Gabriel A. Rabinovich Matías Ostrowski A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection mBio galectin-1 human immunodeficiency virus extracellular vesicles viral reservoir chronic inflammation |
| title | A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection |
| title_full | A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection |
| title_fullStr | A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection |
| title_full_unstemmed | A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection |
| title_short | A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection |
| title_sort | dynamic interplay of circulating extracellular vesicles and galectin 1 reprograms viral latency during hiv 1 infection |
| topic | galectin-1 human immunodeficiency virus extracellular vesicles viral reservoir chronic inflammation |
| url | https://journals.asm.org/doi/10.1128/mbio.00611-22 |
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