| Autor: |
Rubione J; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Pérez PS; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Czernikier A; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Duette GA; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Pereyra Gerber FP; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Salido J; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Fabiano MP; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Ghiglione Y; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Turk G; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Laufer N; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Cagnoni AJ; Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.; Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Pérez Sáez JM; Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Merlo JP; Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Pascuale C; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina., Stupirski JC; Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Sued O; Fundación Huésped, Buenos Aires, Argentina., Varas-Godoy M; Cancer Cell Biology Lab, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., Lewin SR; The Peter Doherty Institute for Infection and Immunity, The University of Melbournegrid.1008.9 and Royal Melbourne Hospital, Melbourne, Victoria, Australia.; Victorian Infectious Diseases Service, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.; Department of Infectious Diseases, Alfred Health and Monash University, Melbourne, Victoria, Australia., Mariño KV; Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina., Rabinovich GA; Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina.; Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina., Ostrowski M; Facultad de Medicina, Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Universidad de Buenos Aires (UBA), Buenos Aires, Argentina.; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. |
| Abstrakt: |
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. |
