S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo

Fernando Real, Aiwei Zhu, Boxin Huang, Ania Belmellat, Alexis Sennepin, Thomas Vogl, Céline Ransy, Marc Revol, Riccardo Arrigucci, Anne Lombès, Johannes Roth, Maria Laura Gennaro, Frédéric Bouillaud, Sarra Cristofari and Morgane Bomsel ()
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Fernando Real: Université Paris Cité
Aiwei Zhu: Université Paris Cité
Boxin Huang: Université Paris Cité
Ania Belmellat: Université Paris Cité
Alexis Sennepin: Université Paris Cité
Thomas Vogl: University of Münster
Céline Ransy: CNRS, UMR8104
Marc Revol: Saint Louis Hospital
Riccardo Arrigucci: The State University of New Jersey
Anne Lombès: CNRS, UMR8104
Johannes Roth: University of Münster
Maria Laura Gennaro: The State University of New Jersey
Frédéric Bouillaud: CNRS, UMR8104
Sarra Cristofari: Saint Louis Hospital
Morgane Bomsel: Université Paris Cité

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract HIV-1 eradication is hindered by viral persistence in cell reservoirs, established not only in circulatory CD4+T-cells but also in tissue-resident macrophages. The nature of macrophage reservoirs and mechanisms of persistence despite combined anti-retroviral therapy (cART) remain unclear. Using genital mucosa from cART-suppressed HIV-1-infected individuals, we evaluated the implication of macrophage immunometabolic pathways in HIV-1 persistence. We demonstrate that ex vivo, macrophage tissue reservoirs contain transcriptionally active HIV-1 and viral particles accumulated in virus-containing compartments, and harbor an inflammatory IL-1R+S100A8+MMP7+M4-phenotype prone to glycolysis. Reactivation of infectious virus production and release from these reservoirs in vitro are induced by the alarmin S100A8, an endogenous factor produced by M4-macrophages and implicated in “sterile” inflammation. This process metabolically depends on glycolysis. Altogether, inflammatory M4-macrophages form a major tissue reservoir of replication-competent HIV-1, which reactivate viral production upon autocrine/paracrine S100A8-mediated glycolytic stimulation. This HIV-1 persistence pathway needs to be targeted in future HIV eradication strategies.

Date: 2022
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DOI: 10.1038/s41467-022-33401-x

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