HIV-1 infection induces Vif-mediated SUMOylation of host RNA splicing factors important for proper viral RNA splicing.

SUMOylation is a dynamically regulated post-translational modification involving covalent attachment of small ubiquitin-like modifiers (SUMOs) to lysine residues of target proteins. SUMOylation modulates multiple fundamental host cellular pathways, including pathways hijacked by HIV-1 to enable replication, but has not been explored by large-scale proteomics in the context of HIV-1 infection. Here, we performed a proteome-wide, mass spectrometry-based screen to identify proteins that are SUMOylated in response to HIV-1 infection. We show that infection with HIV-1 leads to the widespread increased SUMOylation of the heterogeneous nuclear ribonucleoprotein (HNRNP) A/B family. This phenotype was driven by expression of HIV-1 Viral Infectivity Factor (Vif), suggesting an unexplored function for this protein. Depletion of HNRNP A/B proteins led to altered splicing of HIV-1 viral RNAs and dramatically reduced HIV-1 infectivity. Our data suggest a mechanism involving HIV-1-induced, Vif-mediated SUMOylation of host RNA splicing factors as a means to regulate HIV-1 alternative splicing.