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Publication Detail

Title: N6-methyladenosine modification of HIV-1 RNA suppresses type-I interferon induction in differentiated monocytic cells and primary macrophages.

Authors: Chen, Shuliang; Kumar, Sameer; Espada, Constanza E; Tirumuru, Nagaraja; Cahill, Michael P; Hu, Lulu; He, Chuan; Wu, Li

Published In PLoS Pathog, (2021 03)

Abstract: N6-methyladenosine (m6A) is a prevalent RNA modification that plays a key role in regulating eukaryotic cellular mRNA functions. RNA m6A modification is regulated by two groups of cellular proteins, writers and erasers that add or remove m6A, respectively. HIV-1 RNA contains m6A modifications that modulate viral infection and gene expression in CD4+ T cells. However, it remains unclear whether m6A modifications of HIV-1 RNA modulate innate immune responses in myeloid cells that are important for antiviral immunity. Here we show that m6A modification of HIV-1 RNA suppresses the expression of antiviral cytokine type-I interferon (IFN-I) in differentiated human monocytic cells and primary monocyte-derived macrophages. Transfection of differentiated monocytic U937 cells with HIV-1 RNA fragments containing a single m6A-modification significantly reduced IFN-I mRNA expression relative to their unmodified RNA counterparts. We generated HIV-1 with altered m6A levels of RNA by manipulating the expression of the m6A erasers (FTO and ALKBH5) or pharmacological inhibition of m6A addition in virus-producing cells, or by treating HIV-1 RNA with recombinant FTO in vitro. HIV-1 RNA transfection or viral infection of differentiated U937 cells and primary macrophages demonstrated that HIV-1 RNA with decreased m6A levels enhanced IFN-I expression, whereas HIV-1 RNA with increased m6A modifications had opposite effects. Our mechanistic studies indicated that m6A of HIV-1 RNA escaped retinoic acid-induced gene I (RIG-I)-mediated RNA sensing and activation of the transcription factors IRF3 and IRF7 that drive IFN-I gene expression. Together, these findings suggest that m6A modifications of HIV-1 RNA evade innate immune sensing in myeloid cells.

PubMed ID: 33690734 Exiting the NIEHS site

MeSH Terms: Adenosine/analogs & derivatives; Adenosine/metabolism; Gene Expression Regulation/immunology; HIV Infections/immunology*; HIV-1/immunology; HIV-1/metabolism*; Humans; Immunity, Innate/immunology; Interferon Type I/biosynthesis*; Macrophages/metabolism; Macrophages/virology; Monocytes/metabolism; Monocytes/virology; Myeloid Cells/immunology; Myeloid Cells/metabolism; Myeloid Cells/virology*; RNA Processing, Post-Transcriptional/immunology*; RNA, Viral/immunology; RNA, Viral/metabolism*

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