Reassessing APOBEC3G Inhibition by HIV-1 Vif-Derived Peptides

Christopher M. Richards, Ming Li, Angela L. Perkins, Anurag Rathore, Daniel A. Harki, Reuben S. Harris

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

The human APOBEC3G (A3G) enzyme restricts HIV-1 in the absence of the viral accessory protein viral infectivity factor (Vif) by deaminating viral cDNA cytosines to uracils. These uracil lesions base-pair with adenines during the completion of reverse transcription and result in A3G signature G-to-A mutations in the viral genome. Vif protects HIV-1 from A3G-mediated restriction by forming an E3-ubiquitin ligase complex to polyubiquitinate A3G and trigger its degradation. Prior studies indicated that Vif may also directly block the enzymatic activity of A3G and, provocatively, that Vif-derived peptides, Vif 25–39 and Vif 105–119, are similarly inhibitory. Here, we show that Vif 25–39 does not inhibit A3G enzymatic activity and that the inhibitory effect of Vif 105–119 and that of a shorter derivative Vif 107–115, although recapitulated, are non-specific. We also elaborate a simple method for assaying DNA cytosine deaminase activity that eliminates potential polymerase chain reaction-induced biases. Our results show that these Vif-derived peptides are unlikely to be useful as tools to study A3G function or as leads for the development of future therapeutics.

Original languageEnglish (US)
Pages (from-to)88-96
Number of pages9
JournalJournal of Molecular Biology
Volume429
Issue number1
DOIs
StatePublished - Jan 6 2017

Bibliographical note

Funding Information:
We thank the NIH AIDS Reagent Program, Division of AIDS, National Institute for Allergy and Infectious Disease (NIAID), NIH, for the HIV-1 Consensus B Vif Peptide Set. This research was supported by grants from the National Institute of General Medical Sciences (P01-GM091743 to R.S.H. and R01-GM110129 to D.A.H.) and the NIAID (R37-AI064046 to R.S.H.). Partial salary support for C.R. was provided by the Pharmacology Graduate Program and subsequently by a NIAID training grant (T32-AI83196; IMV Training Program). R.S.H. is an Investigator of the Howard Hughes Medical Institute.

Keywords

  • DNA cytosine deamination
  • Evolvability
  • HIV-1
  • Mutation
  • Vif-derived peptides

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