Polymorphism in human APOBEC3H affects a phenotype dominant for subcellular localization and antiviral activity

The APOBEC3 family of cytidine deaminases is part of the innate host defense targeted toward retroviruses and retroelements. APOBEC3H is the most distantly related member of the family and carries functional polymorphisms in current human populations. Haplotype II of APOBEC3H, which is more commonly found in individuals of African descent, encodes a protein with the highest antiviral activity in cells, whereas the other haplotypes encode proteins with weak or no antiviral activity. Here, we show that the different human APOBEC3H haplotypes exhibit differential subcellular localizations, as the haplotype I protein is mostly found in the nucleus and the haplotype II protein is mostly localized to the cytoplasm. The determinant responsible for this phenotype maps to a single amino acid that is also important for APOBEC3H protein stability. Furthermore, we show that the cytoplasmic localization is dominant over nuclear localization, by using fusion proteins of APOBEC3H. Our data support a model in which the APOBEC3H protein encoded by haplotype II is actively retained in the cytoplasm by interacting with specific host factors, whereas the less active protein encoded by haplotype I is allowed to enter the nucleus by a passive mechanism. Together, cytoplasmic localization and its link with protein stability correlate with the ability of APOBEC3H to inhibit HIV replication, providing a mechanistic basis for the differential antiviral activities of different APOBEC3H haplotypes.