Codon-usage-based Inhibition of HIV Protein Synthesis by Human Schlafen 11

Nature. 2012 Nov 1;491(7422):125-8. doi: 10.1038/nature11433. Epub 2012 Sep 23.

Abstract

In mammals, one of the most pronounced consequences of viral infection is the induction of type I interferons, cytokines with potent antiviral activity. Schlafen (Slfn) genes are a subset of interferon-stimulated early response genes (ISGs) that are also induced directly by pathogens via the interferon regulatory factor 3 (IRF3) pathway. However, many ISGs are of unknown or incompletely understood function. Here we show that human SLFN11 potently and specifically abrogates the production of retroviruses such as human immunodeficiency virus 1 (HIV-1). Our study revealed that SLFN11 has no effect on the early steps of the retroviral infection cycle, including reverse transcription, integration and transcription. Rather, SLFN11 acts at the late stage of virus production by selectively inhibiting the expression of viral proteins in a codon-usage-dependent manner. We further find that SLFN11 binds transfer RNA, and counteracts changes in the tRNA pool elicited by the presence of HIV. Our studies identified a novel antiviral mechanism within the innate immune response, in which SLFN11 selectively inhibits viral protein synthesis in HIV-infected cells by means of codon-bias discrimination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Cells, Cultured
  • Codon / genetics*
  • Codon / immunology
  • Gene Expression Regulation, Viral / genetics*
  • HEK293 Cells
  • HIV-1 / genetics*
  • HIV-1 / growth & development
  • HIV-1 / immunology
  • HIV-1 / metabolism
  • Humans
  • Immunity, Innate
  • Nuclear Proteins / immunology
  • Nuclear Proteins / metabolism*
  • Protein Biosynthesis / genetics*
  • Protein Biosynthesis / immunology
  • RNA, Transfer / genetics
  • RNA, Transfer / metabolism
  • RNA, Viral / genetics
  • RNA, Viral / metabolism
  • Reverse Transcription
  • Species Specificity
  • Substrate Specificity
  • Viral Proteins / biosynthesis*
  • Viral Proteins / genetics*
  • Virus Integration

Substances

  • Codon
  • Nuclear Proteins
  • RNA, Viral
  • SLFN11 protein, human
  • Viral Proteins
  • RNA, Transfer