Extracellular vesicles carrying HIV-1 Nef induce trained immunity in myeloid cells

Dubrovsky, L.; Brichacek, B.; Prashant, N. M.; Pushkarsky, T.; Mukhamedova, N.; Dragoljevic, D.; Fitzgerald, M.; Horvath, A.; Murphy, A. J.; Sviridov, D.; Bukrinsky, M. I.

doi:10.1101/2022.06.24.497538

bioRxiv · 10.1101/2022.06.24.497538

Extracellular vesicles carrying HIV-1 Nef induce trained immunity in myeloid cells

Dubrovsky, L.·Brichacek, B.·Prashant, N. M.·Pushkarsky, T.·Mukhamedova, N.·Dragoljevic, D.·Fitzgerald, M.·Horvath, A.·Murphy, A. J.·Sviridov, D.·Bukrinsky, M. I.

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Abstract

SummaryPersistent inflammation is a hallmark of HIV infection and is not reversed after suppression of viral replication by anti-retroviral therapy (ART). One explanation for chronic inflammation in ART-treated HIV-infected individuals is hyperreactivity of the myeloid cells due to a phenomenon called trained immunity. Here, we demonstrate that human monocyte derived macrophages originating from monocytes initially treated with extracellular vesicles containing HIV-1 protein Nef (exNef), but differentiating in the absence of exNef, released increased levels of pro-inflammatory cytokines after lipopolysaccharide stimulation. This effect was associated with epigenetic changes related to inflammation and cholesterol metabolism pathways, upregulation of the lipid rafts, and was blocked by methyl-{beta}-cyclodextrin, statin, and inhibitor of activity of lipid raft-associated receptor IGF1R. Bone marrow-derived macrophages from exNef-injected mice had higher abundance of lipid rafts and produced elevated levels of TNF. These phenomena are consistent with trained immunity and may contribute to persistent inflammation and co-morbidities in HIV-infected individuals.

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Dubrovsky, L., Brichacek, B., Prashant, N. M., Pushkarsky, T., Mukhamedova, N., Dragoljevic, D., Fitzgerald, M., Horvath, A., Murphy, A. J., Sviridov, D., Bukrinsky, M. I.. 2022-06-28. Extracellular vesicles carrying HIV-1 Nef induce trained immunity in myeloid cells. https://doi.org/10.1101/2022.06.24.497538

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