APOBEC3 family DNA cytosine deaminases provide overlapping defenses against pathogen infections. However, most viruses have elaborate evasion mechanisms such as the HIV-1 Vif protein, which subverts cellular CBF-β and a polyubiquitin ligase complex to neutralize these enzymes. Despite advances in APOBEC3 and Vif biology, a full understanding of this direct host-pathogen conflict has been elusive. We combine virus adaptation and computational studies to interrogate the APOBEC3F-Vif interface and build a robust structural model. A recurring compensatory amino acid substitution from adaptation experiments provided an initial docking constraint, and microsecond molecular dynamic simulations optimized interface contacts. Virus infectivity experiments validated a long-lasting electrostatic interaction between APOBEC3F E289 and HIV-1 Vif R15. Taken together with mutagenesis results, we propose a wobble model to explain how HIV-1 Vif has evolved to bind different APOBEC3 enzymes and, more generally, how pathogens may evolve to escape innate host defenses.
Bibliographical noteFunding Information:
We thank the AIDS Research and Reference Reagent Program for materials. This research was supported by the National Institute of Allergy and Infectious Diseases (NIAID) R01 AI064046 and the National Institute of General Medical Sciences (NIGMS) P01 GM091743 to R.S.H. Partial salary support was provided by NIGMS T32 GM008244 (University of Minnesota Medical Scientist Training Program) and National Institute on Drug Abuse (NIDA) F30 DA026310 to J.S. Albin, NIAID T32 AI83196 (IMV Training Program) to C.R., and NIH T32 AI007313 (Immunology Training Program) and NIAID F31 AI116305 to B.D.A. The computational components were funded in part by the NIH Director’s New Innovator Award Program DP2-OD007237, National Biomedical Computation Resource NIH P41 GM103426, and National Science Foundation (NSF) XSEDE Supercomputer resources grant RAC CHE060073N to R.E.A. R.S.H. is an Investigator of the Howard Hughes Medical Institute.
© 2015 The Authors.
Copyright 2018 Elsevier B.V., All rights reserved.
- APOBEC3F-Vif interface
- Pathogen-host interaction