Internal RNA 2′O-methylation in the HIV-1 genome counteracts ISG20 nuclease-mediated antiviral effect. Issue 6 (10th November 2022)

• Record Type: Journal Article
• Authors: El Kazzi, Priscila; Rabah, Nadia; Chamontin, Célia; Poulain, Lina; Ferron, François; Debart, Françoise; Canard, Bruno; Missé, Dorothée; Coutard, Bruno; Nisole, Sébastien; Decroly, Etienne
• Is Part Of: Nucleic acids research. Volume 51:Issue 6(2023)
• Page Start: 2501
• Page End: 2515
• Publication Date: 2022-11-10
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkac996
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: RNA 2′O-methylation is a 'self' epitranscriptomic modification allowing discrimination between host and pathogen. Indeed, human immunodeficiency virus 1 (HIV-1) induces 2′O-methylation of its genome by recruiting the cellular FTSJ3 methyltransferase, thereby impairing detection by RIG-like receptors. Here, we show that RNA 2′O-methylations interfere with the antiviral activity of interferon-stimulated gene 20-kDa protein (ISG20). Biochemical experiments showed that ISG20-mediated degradation of 2′O-methylated RNA pauses two nucleotides upstream of and at the methylated residue. Structure-function analysis indicated that this inhibition is due to steric clash between ISG20 R53 and D90 residues and the 2′O-methylated nucleotide. We confirmed that hypomethylated HIV-1 genomes produced in FTSJ3-KO cells were more prone to in vitro degradation by ISG20 than those produced in cells expressing FTSJ3. Finally, we found that reverse-transcription of hypomethylated HIV-1 was impaired in T cells by interferon-induced ISG20, demonstrating the direct antagonist effect of 2′O-methylation on ISG20-mediated antiviral activity. Lay Summary: Despite highly effective antiretroviral therapies, the human immunodeficiency virus (HIV-1) remains a major public health threat. Its pathogenesis depends on its ability to establish a persistent infection in cells of the immune system. Our study highlights a new insight into how HIV-1 evades early restriction by the immune system. We showed that 2′O-methylation marks found inside HIV-1 RNA promote viral evasion from the antiviral action of the interferon-stimulated gene 20-kDa protein (ISG20), an innate immune restriction factor with a nuclease activity. By disrupting the level of 2′O-methylation of the HIV-1 genome, we demonstrated that ISG20 impairs the reverse transcription process of hypomethylated viruses, as a result of viral RNA decay. Graphical Abstract: