Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest
Sara Marelli,
James C Williamson,
Anna V Protasio,
Adi Naamati,
Edward JD Greenwood,
Janet E Deane,
Paul J Lehner,
Nicholas J Matheson
Affiliations
Sara Marelli
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom
James C Williamson
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom
Anna V Protasio
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom
Adi Naamati
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom
Department of Clinical Neuroscience, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, United Kingdom
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom
Department of Medicine, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, United Kingdom
The seminal description of the cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. We recently reported that HIV-1 Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E; Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.
