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Persistent viral control status is associated with enhanced innate immune responses in people with HIV-1.

iScience

Authors: Jéssica C Dos Santos, Albert L Groenendijk, Suzanne D E Ruijten, Rainer Knoll, Nadira Vadaq, Rob Ter Horst, Ezio T Fok, Wojciech Witkowski, Marc J T Blaauw, Louise E van Eekeren, Wilhelm A J W Vos, Maartje Cleophas-Jacobs, Stephan Reichl, Twan Otten, Joost H A Martens, Arnold van der Meer, Han Koninkx, Marien I de Jonge, Marc D Beyer, Jan van Lunzen, Leo A B Joosten, Christoph Bock, Casper Rokx, Annelies Verbon, Linos Vandekerckhove, Anna C Aschenbrenner, Joachim L Schultze, Vasiliki Matzaraki, Andre J A M van der Ven, Mihai G Netea

The mechanisms mediating elite and persistent HIV control in people living with HIV (PLHIV) are only partially understood and largely attributed to adaptive T cell responses, but whether innate immunity also contributes remains unclear. Using samples from the 2000HIV study, we examined the transcriptional and functional profiles of monocytes from spontaneous HIV controllers and normal progressors on long-term antiretroviral therapy. HIV controllers displayed enhanced cytokine production after bacterial and viral stimulation, alongside antiviral and interferon-inducible transcriptional signatures and reduced inflammatory gene expression. Persistent controllers further showed increased capacity for trained immunity, with H3K4me3 profiling indicating the epigenetic priming of innate immune genes. Remarkably, relatives of persistent controllers also exhibited stronger innate and trained immune responses than relatives of normal progressors. These findings suggest that robust innate immunity, particularly monocyte function, may precede infection and contribute to sustained HIV control, offering new avenues for therapies that induce similar innate antiviral responses.

© 2026 The Authors.

PMID: 41816294

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