Catalytic activity of APOBEC3F is required for efficient restriction of Vif-deficient human immunodeficiency virus

•Catalytic activity of A3F is required for efficient restriction of Vif-deficient HIV.•Stably expressed A3F restricts HIV Vif mutants selectively susceptible to A3F.•Putative A3F/G-interaction Vif mutants show divergent spreading infection phenotypes.

APOBEC3 proteins are DNA cytosine deaminases that restrict the replication of human immunodeficiency virus deficient in the counterdefense protein Vif. Here, we address the capacity of APOBEC3F to restrict via deaminase-dependent and -independent mechanisms by monitoring spreading infections in diverse T cell lines. Our data indicate that only a deaminase-proficient protein is capable of long-term restriction of Vif-deficient HIV in T cells, analogous to prior reports for APOBEC3G. This indicates that the principal mechanism of APOBEC3F restriction is deaminase-dependent.