APOBEC3G inhibits HIV-1 RNA elongation by inactivating the viral trans-activation response element

Roni Nowarski, Ponnandy Prabhu, Edan Kenig, Yoav Smith, Elena Britan-Rosich, Moshe Kotler*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Deamination of cytidine residues in viral DNA is a major mechanism by which APOBEC3G (A3G) inhibits vif-deficient human immunodeficiency virus type 1 (HIV-1) replication. dC-to-dU transition following RNase-H activity leads to viral cDNA degradation, production of non-functional proteins, formation of undesired stop codons and decreased viral protein synthesis. Here, we demonstrate that A3G provides an additional layer of defense against HIV-1 infection dependent on inhibition of proviral transcription. HIV-1 transcription elongation is regulated by the trans-activation response (TAR) element, a short stem-loop RNA structure required for elongation factors binding. Vif-deficient HIV-1-infected cells accumulate short viral transcripts and produce lower amounts of full-length HIV-1 transcripts due to A3G deamination of the TAR apical loop cytidine, highlighting the requirement for TAR loop integrity in HIV-1 transcription. We further show that free single-stranded DNA (ssDNA) termini are not essential for A3G activity and a gap of CCC motif blocked with juxtaposed DNA or RNA on either or 3′ + 5′ ends is sufficient for A3G deamination. These results identify A3G as an efficient mutator and that deamination of (-)SSDNA results in an early block of HIV-1 transcription.

Original languageEnglish
Pages (from-to)2840-2853
Number of pages14
JournalJournal of Molecular Biology
Volume426
Issue number15
DOIs
StatePublished - 29 Jul 2014

Keywords

  • APOBEC3G
  • deamination
  • HIV-1
  • ssDNA
  • Tat

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