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2026

EMBO Rep 2026 Jun 15. doi: 10.1038/s44319-026-00838-w. Online ahead of print.

HIV-1 Nef generates lasting innate immune memory in haematopoietic stem and progenitor cells in vivo

Andrew J Fleetwood, Nigora Mukhamedova, Dragana Dragoljevic, Man K S Lee, Yangsong Xu, Malathi S I Dona, Ian Hsu, Camilla Bertuzzo Veiga, Fumihiko Takeuchi, Ben Crossett, Denise Tran, Alexander R Pinto, Michael Bukrinsky, Andrew J Murphy, Dmitri Sviridov

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia. School of Agriculture, Biomedicine and Environment, Baker Department of Cardiovascular Research, Translation and Implementation, La Trobe University, Bundoora, VIC, Australia. Sydney Mass Spectrometry, The University of Sydney, Camperdown, NSW, Australia. Department of Microbiology, Immunology and Tropical Diseases, George Washington University, Washington DC, USA. Baker Heart and Diabetes Institute, Melbourne, VIC, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.

Service type: Stock strains

Abstract

HIV infection is accompanied by chronic inflammation-related co-morbidities, even when viral replication is suppressed by therapy. This persistent inflammatory state suggests that long-lived immune cell lineages may acquire stable pro-inflammatory programming. Here, we investigate whether inflammatory programming can be imprinted within hematopoietic lineages, following the exposure of mice and bone marrow-derived macrophages (BMDMs) to extracellular vesicles (EVs) carrying Nef, a key inflammatory factor of HIV. Multi-omics profiling shows that hematopoietic cells exposed to Nef-EVs undergo epigenetic remodeling and reprogramming of energy and lipid metabolism characteristic of trained innate immunity. The inflammatory phenotype in BMDMs is partially reversed by inhibition of glycolysis, a key metabolic driver of trained immunity. We demonstrate that following competitive bone marrow transplantation, hematopoiesis in mice receiving bone marrow from Nef-EV-treated donors displays a sustained bias toward myelopoiesis, and BMDMs retain enhanced inflammatory potential. These findings demonstrate that Nef-EVs can imprint a lasting inflammatory memory, mechanistically similar to trained immunity, in hematopoietic cells. This memory persists beyond the initial exposure and may contribute to chronic inflammation in people with HIV.