Abstract
HIV-1 encodes the accessory protein Vif, which hijacks a host Cullin-RING ubiquitin ligase (CRL) complex as well as the non-canonical cofactor CBFβ, to antagonize APOBEC3 antiviral proteins. Non-canonical cofactor recruitment to CRL complexes by viral factors, to date, has only been attributed to HIV-1 Vif. To further study this phenomenon, we employed a comparative approach combining proteomic, biochemical, structural, and virological techniques to investigate Vif complexes across the lentivirus genus, including primate (HIV-1 and simian immunodeficiency virus macaque [SIVmac]) and non-primate (FIV, BIV, and MVV) viruses. We find that CBFβ is completely dispensable for the activity of non-primate lentiviral Vif proteins. Furthermore, we find that BIV Vif requires no cofactor and that MVV Vif requires a novel cofactor, cyclophilin A (CYPA), for stable CRL complex formation and anti-APOBEC3 activity. We propose modular conservation of Vif complexes allows for potential exaptation of functions through the acquisition of non-CRL-associated host cofactors while preserving anti-APOBEC3 activity.
Highlights
Viruses must overcome host challenges to replicate successfully in an infected host
In order to determine which host factors are physically bound to Vif proteins across the lentivirus phylogeny, we employed an unbiased proteomic approach using Affinity purifications (AP)-MS to study five divergent Vif proteins from maedi visna virus (MVV), bovine immunodeficiency virus (BIV), feline immunodeficiency virus (FIV), SIVmac, and human immunodeficiency virus 1 (HIV-1) (Table S1)
Putative interactions identified by AP-MS were scored using the significance analysis of interactome (SAINT) algorithm (Choi et al, 2011), and interactions with a SAINT probability score ≥ 0.9 in at least one Vif dataset were included (Table S2)
Summary
Viruses must overcome host challenges to replicate successfully in an infected host. These challenges include the mechanics of viral entry, genetic replication, assembly, and budding, and a variety of host defined replication barriers, both innate and adaptive. An effective method for mapping host-pathogen interactions involves affinity purification of epitope-tagged viral proteins from host cells followed by mass spectrometry (AP-MS) to identify interacting host factors. This approach has been used to map global host-pathogen PPIs for HIV-1 (Jäger et al, 2012a), Herpes (Davis et al, 2015), and Hepatitis C (Ramage et al, 2015), as well as to study the PPIs of individual viral proteins in HPV (Tan et al, 2012; White et al, 2012a, 2012b), influenza (York et al, 2014), and picornaviruses (Greninger et al, 2012). These types of proteomic analyses have focused on a single virus or closely related sets of viruses, and typically from the same (human) host
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