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Journal of Virology, November 2008, p. 10998-11008, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.01311-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mouse APOBEC3 Restricts Friend Leukemia Virus Infection and Pathogenesis In Vivo{triangledown}

Eri Takeda,1 Sachiyo Tsuji-Kawahara,1 Mayumi Sakamoto,1 Marc-André Langlois,2 Michael S. Neuberger,2 Cristina Rada,2 and Masaaki Miyazawa1*

Department of Immunology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan,1 Medical Research Council, Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, United Kingdom2

Received 24 June 2008/ Accepted 3 September 2008

Several members of the apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like complex 3 (APOBEC3) family in primates act as potent inhibitors of retroviral replication. However, lentiviruses have evolved mechanisms to specifically evade host APOBEC3. Likewise, murine leukemia viruses (MuLV) exclude mouse APOBEC3 from the virions and cleave virion-incorporated APOBEC3. Although the betaretrovirus mouse mammary tumor virus has been shown to be susceptible to mouse APOBEC3, it is not known if APOBEC3 has a physiological role in restricting more widely distributed and long-coevolved mouse gammaretroviruses. The pathogenicity of Friend MuLV (F-MuLV) is influenced by several host genes: some directly restrict the cell entry or integration of the virus, while others influence the host immune responses. Among the latter, the Rfv3 gene has been mapped to chromosome 15 in the vicinity of the APOBEC3 locus. Here we have shown that polymorphisms at the mouse APOBEC3 locus indeed influence F-MuLV replication and pathogenesis: the APOBEC3 alleles of F-MuLV-resistant C57BL/6 and -susceptible BALB/c mice differ in their sequences and expression levels in the hematopoietic tissues and in their abilities to restrict F-MuLV replication both in vitro and in vivo. Furthermore, upon infection with the pathogenic Friend virus complex, (BALB/c x C57BL/6)F1 mice displayed an exacerbated erythroid cell proliferation when the mice carried a targeted disruption of the C57BL/6-derived APOBEC3 allele. These results indicate, for the first time, that mouse APOBEC3 is a physiologically functioning restriction factor to mouse gammaretroviruses.

* Corresponding author. Mailing address: Department of Immunology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan. Phone and fax: 81-72-367-7600. E-mail: masaaki{at}med.kindai.ac.jp

{triangledown} Published ahead of print on 10 September 2008.

Journal of Virology, November 2008, p. 10998-11008, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.01311-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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