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Journal of Virology, February 2008, p. 1305-1313, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01371-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Species-Specific Restriction of Apobec3-Mediated Hypermutation{triangledown}

Edward P. Browne1,3 and Dan R. Littman1,2,3*

The Kimmel Center for Biology and Medicine of the Skirball Institute,1 Howard Hughes Medical Institute,2 Departments of Pathology and Microbiology, New York University School of Medicine, New York, New York 100163

Received 24 June 2007/ Accepted 8 November 2007

Apobec proteins are a family of cellular cytidine deaminases, among which several members have been shown to have potent antiviral properties. This antiviral activity is associated with the ability to cause hypermutation of retroviral cDNA. However, recent research has indicated that Apobec proteins are also able to inhibit retroviruses by other mechanisms that are independent of their deaminase activity. We have compared the antiviral activities of human and murine Apobec3 (A3) proteins, and we have found that, consistent with previous reports, human immunodeficiency virus (HIV) is able to resist human A3G but is sensitive to murine A3, whereas murine leukemia virus (MLV) is relatively resistant to murine A3 (mA3) but sensitive to human A3G. In contrast to previous studies, we observed that mA3 is packaged efficiently into MLV particles. The C-terminal cytidine deaminase domain (CDD2) is required for packaging of mA3 into MLV particles, and packaging did not depend on the MLV viral RNA. However, mA3 packed into MLV particles failed to cause hypermutation of viral DNA, indicating that its deaminase activity is blocked or inhibited. hA3G also caused significantly less hypermutation of MLV than of HIV DNA. Both mA3 and the splice variant mA3{Delta}5 exhibited some residual antiviral activity against MLV and caused a reduction in the ability of MLV particles to generate reverse transcription products. These results suggest that MLV has evolved specific mechanisms to block the ability of Apobec proteins to mediate deaminase-dependent hypermutation.

* Corresponding author. Mailing address: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, 540 First Ave., Second Floor, New York, NY 10016. Phone: (212) 263-7579. Fax: (212) 263-5711. E-mail: littman{at}saturn.med.nyu.edu

{triangledown} Published ahead of print on 21 November 2007.

Journal of Virology, February 2008, p. 1305-1313, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01371-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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