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Journal of Virology, April 2006, p. 3853-3862, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.3853-3862.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Adaptive Evolution and Antiviral Activity of the Conserved Mammalian Cytidine Deaminase APOBEC3H

Molly OhAinle,1,3 Julie A. Kerns,2 Harmit S. Malik,2 and Michael Emerman2,3*

Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98109,1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,2 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 981093

Received 28 November 2005/ Accepted 30 January 2006

The APOBEC3 genes encode cytidine deaminases that act as components of an intrinsic immune defense that have potent activity against a variety of retroelements. This family of genes has undergone a rapid expansion from one or two genes in nonprimate mammals to at least seven members in primates. Here we describe the evolution and function of an uncharacterized antiviral effector, APOBEC3H, which represents the most evolutionarily divergent APOBEC3 gene found in primates. We found that APOBEC3H has undergone significant adaptive evolution in primates. Consistent with our previous findings implicating adaptively evolving APOBEC3 genes as antiviral effectors, APOBEC3H from Old World monkeys (OWMs) has efficient antiviral activity against primate lentiviruses, is sensitive to inactivation by the simian immunodeficiency virus Vif protein, and is capable of hypermutating retroviral genomes. In contrast, human APOBEC3H is inherently poorly expressed in primate cells and is ineffective at inhibiting retroviral replication. Both OWM and human APOBEC3H proteins can be expressed in bacteria, where they display significant DNA mutator activity. Thus, humans have retained an APOBEC3H gene that encodes a functional, but poorly expressed, cytidine deaminase with no apparent antiviral activity. The consequences of the lack of antiviral activity of human APOBEC3H are likely to be relevant to the current-day abilities of humans to combat retroviral challenges.

* Corresponding author. Mailing address: Division of Human Biology, Mailstop C2-023, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N, P.O. Box 10924, Seattle, WA 98109-1024. Phone: (206) 667-5058. Fax: (206) 667-6523. E-mail: memerman{at}fhcrc.org.

Journal of Virology, April 2006, p. 3853-3862, Vol. 80, No. 8
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.8.3853-3862.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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