A chimeric human APOBEC3A protein with a three amino acid insertion confers differential HIV-1 and adeno-associated virus restriction

- A human APOBEC3A with a three amino acid insertion that restricts HIV-1 is described.
- The insertion is in the AC loop 1 region of APOBEC3A.
- The charge and hydrophobicity of the insertion is independent of restriction.
- The mechanism of restriction appears to be deamination-independent.
- The mechanism likely involves the inhibition of reverse transcription in target cells.

Old World monkey (OWM) and hominid APOBEC3Aproteins exhibit differential restriction activities against lentiviruses and DNA viruses. Human APOBEC3A(hA3A)has weak restriction activity against HIV-1Δvifbut is efficiently restricted by an artificially generated chimeric from mandrills (mndA3A/G). We show that a chimeric hA3Acontaining the “WVS” insertion (hA3A[27WVS29]) conferred potent HIV-1restriction activity. Analysis of each amino acid of the “WVS” motif show that the length and not necessarily the charge or hydrophobicity of the amino acids accounted for restriction activity. Our results suggest that hA3A[27WVS29]restricts HIV-1at the level of reverse transcription in target cells. Finally, our results suggest that insertion of “WVS” into hA3Amodestly reduces restriction of adeno-associated virus 2(AAV-2)while insertion of the AC Loop1region of the mndA3A/G into hA3A abolished AAV-2 restriction, strengthening the role of this molecular interface in the functional evolution of primate A3A.