title: A Single Nucleotide Polymorphism in Human APOBEC3C Enhances Restriction of Lentiviruses.
abstract: Humans express seven human APOBEC3 proteins, which can inhibit viruses and endogenous retroelements through cytidine deaminase activity. The seven paralogs differ in the potency of their antiviral effects, as well as in their antiviral targets. One APOBEC3, APOBEC3C, is exceptional as it has been found to only weakly block viruses and endogenous retroelements compared to other APOBEC3s. However, our positive selection analyses suggest that APOBEC3C has played a role in pathogen defense during primate evolution. Here, we describe a single nucleotide polymorphism in human APOBEC3C, a change from serine to isoleucine at position 188 (I188) that confers potent antiviral activity against HIV-1. The gain-of-function APOBEC3C SNP results in increased enzymatic activity and hypermutation of target sequences when tested in vitro, and correlates with increased dimerization of the protein. The I188 is widely distributed in human African populations, and is the ancestral primate allele, but is not found in chimpanzees or gorillas. Thus, while other hominids have lost activity of this antiviral gene, it has been maintained, or re-acquired, as a more active antiviral gene in a subset of humans. Taken together, our results suggest that APOBEC3C is in fact involved in protecting hosts from lentiviruses.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, United States of America.|Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Cristina J
authors.initials: CJ
authors.lastname: Wittkopp
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Madison B
authors.initials: MB
authors.lastname: Adolph
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Lily I
authors.initials: LI
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Linda
authors.initials: L
authors.lastname: Chelico
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.|Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Emerman
mesh_terms: D000818:Animals; D003564:Cytidine Deaminase / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015658:HIV Infections / Q000235:genetics; D006801:Humans; D016180:Lentivirus Infections / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011323:Primates
chemical_list: C495795:APOBEC3C protein, human; D003564:Cytidine Deaminase