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Journal of Virology, April 2009, p. 3486-3495, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02347-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Induction of APOBEC3 In Vivo Causes Increased Restriction of Retrovirus Infection

Chioma M. Okeoma,¹ Audrey Low,² Will Bailis,¹ Hung Y. Fan,² B. Matija Peterlin,³ and Susan R. Ross^1*

Department of Microbiology and Abramson Family Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104,¹ Department of Molecular Biology and Biochemistry and Cancer Research Institute, University of California at Irvine, Irvine, California,² Rosalind Russell Medical Research Center, Departments of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, California³

Received 11 November 2008/ Accepted 9 January 2009

APOBEC3 proteins are important cellular factors that restrict infection by a number of viruses, including human immunodeficiency virus type 1 (HIV-1). Previously, we found that the mouse APOBEC3 (mA3) restricts infection by mouse mammary tumor virus (MMTV) in its natural host. Dendritic cells (DCs) are the first in vivo targets of MMTV infection. In this study, we demonstrate that mA3 expressed in target cells restricts MMTV infection in DCs ex vivo and in vivo. By comparing infection of DCs from mA3^+/+ and mA3^–/– mice with one-hit viruses, we show that mA3 expression in target cells blocked MMTV infection at a postentry step and acted together with virion-packaged mA3 to inhibit infection. Similar results were obtained upon infection of mouse DCs with HIV-1 cores pseudotyped with vesicular stomatitis virus G protein. In addition, treatment of cells or mice with lipopolysaccharide (LPS) caused increased levels of mA3 expression and rendered them resistant to MMTV infection. Alpha interferon treatment had a similar effect. This LPS-induced resistance to infection was seen only in mA3^+/+ mice and not in mA3^–/– mice, arguing that mA3 is the major anti-MMTV restriction factor that is induced upon DC maturation. Thus, increasing the levels of this intrinsic antiretroviral factor in vivo can lead to increased levels of restriction because of higher levels of both cell-intrinsic as well as virion-packaged APOBEC3.

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* Corresponding author. Mailing address: 313 BRBII/III, University of Pennsylvania, 421 Curie Blvd., Philadelphia, PA 19104-6142. Phone: (215) 898-9764. Fax: (215) 573-2028. E-mail: rosss{at}mail.med.upenn.edu

Published ahead of print on 19 January 2009.

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Journal of Virology, April 2009, p. 3486-3495, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.02347-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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