Long noncoding RNA MIR4435-2HG enhances metabolic function of myeloid dendritic cells from HIV-1 elite controllers

• Published in: The Journal of clinical investigation Vol. 131; no. 9; pp. 1 - 16
• Main Authors: Hartana, Ciputra Adijaya, Rassadkina, Yelizaveta, Gao, Ce, Martin-Gayo, Enrique, Walker, Bruce D, Lichterfeld, Mathias, Yu, Xu G
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 03-05-2021
• Subjects: Biomedical research; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Drug therapy; Epigenesis, Genetic - immunology; Epigenetics; Female; Gene expression; Glycolysis; Glycolysis - immunology; HIV; HIV Infections - immunology; HIV Infections - metabolism; HIV-1 - immunology; HIV-1 - metabolism; Human immunodeficiency virus; Humans; Immune response (cell-mediated); Infections; Lymphocytes; Lymphocytes T; Male; Mechanistic Target of Rapamycin Complex 1 - immunology; Mechanistic Target of Rapamycin Complex 1 - metabolism; Metabolism; MicroRNAs - immunology; MicroRNAs - metabolism; Myeloid Cells - immunology; Myeloid Cells - metabolism; Oxidative Phosphorylation; Phosphorylation; Rapamycin; Regulatory-Associated Protein of mTOR - immunology; Regulatory-Associated Protein of mTOR - metabolism; Respiration; RNA, Long Noncoding - immunology; RNA, Long Noncoding - metabolism; Roles; Signal transduction; Signal Transduction - immunology; TLR3 protein; Toll-like receptors; TOR protein; Viral infections; AIDS/HIV; Innate immunity; Immunology; Dendritic cells; Noncoding RNAs
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI146136

Restriction of HIV-1 replication in elite controllers (ECs) is frequently attributed to T cell-mediated immune responses, while the specific contribution of innate immune cells is less clear. Here, we demonstrate an upregulation of the host long noncoding RNA (lncRNA) MIR4435-2HG in primary myeloid dendritic cells (mDCs) from ECs. Elevated expression of this lncRNA in mDCs was associated with a distinct immunometabolic profile, characterized by increased oxidative phosphorylation and glycolysis activities in response to TLR3 stimulation. Using functional assays, we show that MIR4435-2HG directly influenced the metabolic state of mDCs, likely through epigenetic mechanisms involving H3K27ac enrichment at an intronic enhancer in the RPTOR gene locus, the main component of the mammalian target of rapamycin complex 1 (mTORC1). Together, these results suggest a role of MIR4435-2HG for enhancing immunometabolic activities of mDCs in ECs through targeted epigenetic modifications of a member of the mTOR signaling pathway.