A Dynamic Interplay of Circulating Extracellular Vesicles and Galectin-1 Reprograms Viral Latency during HIV-1 Infection

• Published in: mBio Vol. 13; no. 4; p. e0061122
• Main Authors: Rubione, Julia, Pérez, Paula S., Czernikier, Alejandro, Duette, Gabriel A., Pereyra Gerber, Federico Pehuen, Salido, Jimena, Fabiano, Martina P., Ghiglione, Yanina, Turk, Gabriela, Laufer, Natalia, Cagnoni, Alejandro J., Pérez Sáez, Juan M., Merlo, Joaquín P., Pascuale, Carla, Stupirski, Juan C., Sued, Omar, Varas-Godoy, Manuel, Lewin, Sharon R., Mariño, Karina V., Rabinovich, Gabriel A., Ostrowski, Matías
• Format: Journal Article
• Language: English
• Published: 1752 N St., N.W., Washington, DC American Society for Microbiology 30.08.2022
• Subjects: chronic inflammation; extracellular vesicles; galectin-1; Host-Microbial Interactions; human immunodeficiency virus; Research Article; viral reservoir; human immunodeficiency virus; viral reservoir; extracellular vesicles; chronic inflammation; galectin-1
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.00611-22

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.