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.