title: The AKV murine leukemia virus is restricted and hypermutated by mouse APOBEC3.
abstract: APOBEC3 proteins are potent restriction factors against retroviral infection in primates. This restriction is accompanied by hypermutations in the retroviral genome that are attributable to the cytidine deaminase activity of the APOBEC3 proteins. Studies of nucleotide sequence diversity among endogenous gammaretroviruses suggest that the evolution of endogenous retroelements could have been shaped by the mutagenic cytidine deaminase activity of APOBEC3. In mice, however, APOBEC3 appears to restrict exogenous murine retroviruses in the absence of detectable levels of deamination. AKV is an endogenous retrovirus that is involved in causing a high incidence of thymic lymphoma in AKR mice. A comparative analysis of several mouse strains revealed a relatively low level of APOBEC3 expression in AKR mice. Here we show that endogenous mouse APOBEC3 restricts AKV infection and that this restriction likely reflects polymorphisms affecting APOBEC3 abundance rather than differences in the APOBEC3 isoforms expressed. We also observe that restriction of AKV by APOBEC3 is accompanied by G-->A hypermutations in the viral genome. Our findings demonstrate that APOBEC3 acts as a restriction factor in rodents affecting the strain tropism of AKV, and they provide good support for the proposal that APOBEC3-mediated hypermutation contributed to the evolution of endogenous rodent retroviral genomes.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom CB2 0QH. langlois@uottawa.ca
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Langlois
authors.forename: Kristin
authors.initials: K
authors.lastname: Kemmerich
authors.forename: Cristina
authors.initials: C
authors.lastname: Rada
authors.forename: Michael S
authors.initials: MS
authors.lastname: Neuberger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D003564:Cytidine Deaminase / Q000502:physiology*; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000502:physiology*; D007942:Leukemia, Experimental / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D012192:Retroviridae Infections / Q000821:virology; D017422:Sequence Analysis, DNA; D020539:Sequence Analysis, Protein; D014412:Tumor Virus Infections / Q000821:virology
chemical_list: C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase