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J. Biol. Chem., Vol. 282, Issue 4, 2587-2595, January 26, 2007

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APOBEC3F Can Inhibit the Accumulation of HIV-1 Reverse Transcription Products in the Absence of Hypermutation

COMPARISONS WITH APOBEC3G^*

From the Department of Infectious Diseases, King's College London School of Medicine, London, SE1 9RT, United Kingdom

APOBEC3F (apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1-like protein 3F) is a cytidine deaminase that, like APOBEC3G, is able to restrict the replication of HIV-1/ vif. Initial studies revealed high numbers of mutations in the cDNA of viruses produced in the presence of these proteins, suggesting that cytidine deamination underpinned the inhibition of infection. However, we have recently shown that catalytically inactive APOBEC3G proteins, derived through mutation of the C-terminal cytidine deaminase motif, still exert a substantial antiviral effect. Here, we have generated a panel of APOBEC3F mutant proteins and show that the C-terminal cytidine deaminase motif is essential for catalytic activity and that catalytic activity is not necessary for the antiviral effect of APOBEC3F. Furthermore, we demonstrate that the antiviral activities of wild-type and catalytically inactive APOBEC3F and APOBEC3G proteins correspond well with reductions in the accumulation of viral reverse transcription products. Additional comparisons between APOBEC3F and APOBEC3G suggest that the loss of deaminase activity is more detrimental to APOBEC3G function than to APOBEC3F function, as reflected by perturbations to the suppression of reverse transcript accumulation as well as antiviral activity. Taken together, these data suggest that both APOBEC3F and APOBEC3G are able to function as antiviral factors in the absence of cytidine deamination, that this editing-independent activity is an important aspect of APOBEC protein-mediated antiviral phenotypes, but that APOBEC3F may be a better model in which to study it.

Received for publication, August 1, 2006 , and in revised form, November 10, 2006.

^* This work was supported by the United Kingdom Medical Research Council, the Biotechnology and Biological Sciences Research Council, and the Royal Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Fellow of the European Molecular Biology Organisation.

² Royal Society Dorothy Hodgkin Research Fellow.

³ To whom correspondence should be addressed: Dept. of Infectious Diseases, King's College London School of Medicine, 2nd Floor New Guy's House, Guy's Hospital, London Bridge, London, SE1 9RT, UK. Tel.: 44-20-7188-0149; Fax: 44-20-7188-0147; E-mail: michael.malim{at}kcl.ac.uk.

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