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; Morgane Bomsel

doi:https://doi.org/10.1038/s41467-022-33401-x

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, Morgane Bomsel

New Jersey Medical School (NJMS), Public Health Research Institute Center

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

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.

Original language	American English
Article number	5956
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33401-x
State	Published - Dec 2022

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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https://doi.org/10.1038/s41467-022-33401-x

Cite this

@article{f848531beada4a13ba0922521d6cb8cb,

title = "S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo",

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.",

author = "Fernando Real and Aiwei Zhu and Boxin Huang and Ania Belmellat and Alexis Sennepin and Thomas Vogl and C{\'e}line Ransy and Marc Revol and Riccardo Arrigucci and Anne Lomb{\`e}s and Johannes Roth and Gennaro, {Maria Laura} and Fr{\'e}d{\'e}ric Bouillaud and Sarra Cristofari and Morgane Bomsel",

note = "Funding Information: The authors thank the tissue donors for their kind participation in the study. This study was supported by l{\textquoteright}Agence Nationale de Recherches sur le Sida et les H{\'e}patites Virales (ANRS) (AO2015-2-17046) and SIDACTION (15CONV03), and Fondation pour la Recherche Medicale (Equipe FRM: EQU201903007830) funds to M.B. F.R. received post-doctoral fellowship from SIDACTION and ANRS, A.Z. is a doctoral fellow from the China Scholarship Council (CSC), and A.S. received a post-doctoral fellowship from ANRS. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "https://doi.org/10.1038/s41467-022-33401-x",

language = "American English",

volume = "13",

journal = "Nature communications",

issn = "2041-1723",

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TY - JOUR

T1 - S100A8-mediated metabolic adaptation controls HIV-1 persistence in macrophages in vivo

AU - Real, Fernando

AU - Zhu, Aiwei

AU - Huang, Boxin

AU - Belmellat, Ania

AU - Sennepin, Alexis

AU - Vogl, Thomas

AU - Ransy, Céline

AU - Revol, Marc

AU - Arrigucci, Riccardo

AU - Lombès, Anne

AU - Roth, Johannes

AU - Gennaro, Maria Laura

AU - Bouillaud, Frédéric

AU - Cristofari, Sarra

AU - Bomsel, Morgane

N1 - Funding Information: The authors thank the tissue donors for their kind participation in the study. This study was supported by l’Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS) (AO2015-2-17046) and SIDACTION (15CONV03), and Fondation pour la Recherche Medicale (Equipe FRM: EQU201903007830) funds to M.B. F.R. received post-doctoral fellowship from SIDACTION and ANRS, A.Z. is a doctoral fellow from the China Scholarship Council (CSC), and A.S. received a post-doctoral fellowship from ANRS. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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U2 - https://doi.org/10.1038/s41467-022-33401-x

DO - https://doi.org/10.1038/s41467-022-33401-x

M3 - Article

C2 - 36220814

SN - 2041-1723

VL - 13

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 5956

ER -

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

Abstract

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