Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression

Cell Host Microbe. 2016 May 11;19(5):675-85. doi: 10.1016/j.chom.2016.04.002. Epub 2016 Apr 21.


Covalent addition of a methyl group to adenosine N(6) (m(6)A) is an evolutionarily conserved and common RNA modification that is thought to modulate several aspects of RNA metabolism. While the presence of multiple m(6)A editing sites on diverse viral RNAs was reported starting almost 40 years ago, how m(6)A editing affects virus replication has remained unclear. Here, we used photo-crosslinking-assisted m(6)A sequencing techniques to precisely map several m(6)A editing sites on the HIV-1 genome and report that they cluster in the HIV-1 3' untranslated region (3' UTR). Viral 3' UTR m(6)A sites or analogous cellular m(6)A sites strongly enhanced mRNA expression in cis by recruiting the cellular YTHDF m(6)A "reader" proteins. Reducing YTHDF expression inhibited, while YTHDF overexpression enhanced, HIV-1 protein and RNA expression, and virus replication in CD4+ T cells. These data identify m(6)A editing and the resultant recruitment of YTHDF proteins as major positive regulators of HIV-1 mRNA expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • CD4-Positive T-Lymphocytes / virology
  • Cell Line
  • Cloning, Molecular
  • Gene Expression Regulation, Viral
  • Genome, Viral
  • HEK293 Cells
  • HIV-1 / genetics*
  • HIV-1 / metabolism*
  • Human Immunodeficiency Virus Proteins / genetics
  • Human Immunodeficiency Virus Proteins / metabolism
  • Humans
  • RNA Editing*
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism*
  • RNA, Viral / genetics*
  • RNA, Viral / metabolism*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Virus Replication / drug effects


  • 3' Untranslated Regions
  • Human Immunodeficiency Virus Proteins
  • RNA, Messenger
  • RNA, Viral
  • RNA-Binding Proteins
  • YTHDF2 protein, human