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 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.

• Authors: 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
• Journal: mBio (mBio) Vol. 13 Issue 4 Pg. e0061122 (08 30 2022) ISSN: 2150-7511 [Electronic] United States
• PMID: 35943163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Galectin 1
• RNA

Topics

• CD4-Positive T-Lymphocytes
• Extracellular Vesicles
• Galectin 1 (therapeutic use)
• HIV Infections
• HIV-1 (physiology)
• Humans
• Inflammation
• RNA
• Virus Latency
• Virus Replication