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.