Cellular HIV-1 inhibition by truncated old world primate APOBEC3A proteins lacking a complete deaminase domain

•The APOBEC3A protein from the colobus monkey, De Brazza׳s monkey and mandrill can restrict HIV-1.•Restriction of HIV-1 by colA3A is at a post-integration step.•Restriction of HIV-1 is mediated by amino acid substitutions in the AC-Loop1 region.•These APOBEC3A proteins can be truncated to 100 amino acids and retain restriction activity.

The APOBEC3 (A3) deaminases are retrovirus restriction factors that were proposed as inhibitory components of HIV-1 gene therapy vectors. However, A3 mutational activity may induce undesired genomic damage and enable HIV-1 to evade drugs and immune responses. Here, we show that A3A protein from Colobus guereza (colA3A) can restrict HIV-1 replication in producer cells in a deaminase-independent manner without inducing DNA damage. Neither HIV-1 reverse transcription nor integration were significantly affected by colA3A, but capsid protein synthesis was inhibited. The determinants for colA3A restriction mapped to the N-terminal region. These properties extend to A3A from mandrills and De Brazza׳s monkeys. Surprisingly, truncated colA3A proteins expressing only the N-terminal 100 amino acids effectively exclude critical catalytic regions but retained potent cellular restriction activity. These highlight a unique mechanism of cellular HIV-1 restriction by several Old World monkey A3A proteins that may be exploited for functional HIV-1 cure strategies.