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J. Biol. Chem., Vol. 283, Issue 5, 2518-2525, February 1, 2008

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Vpr.A3A Chimera Inhibits HIV Replication^*

Renato S. Aguiar¹, Nika Lovsin, Amilcar Tanuri^¶, and B. Matija Peterlin²

From the Department of Medicine, Microbiology, and Immunology, University of California at San Francisco, San Francisco, California, 94143-0703, Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia, and ^¶Instituto de Biologia, Departamento de Genética, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21944-970, Brazil

Several APOBEC3 proteins (A3F and A3G), that are cytidine deaminases restrict human immunodeficiency virus (HIV) replication in the absence of the viral infectivity factor (Vif) protein. However, Vif leads to their degradation and counteracts their effects. Another member, A3A, restricts some retrotransposons and another virus but not HIV. We reasoned that this failure was due to the lack of appropriate targeting. Thus, we fused A3A to another viral protein, Vpr, which binds p6 in Gag and is incorporated into viral cores. Indeed, the Vpr.A3A chimera but not A3A was found abundantly in the viral core. It also restricted potently the replication of HIV and simian immunodeficiency virus in the presence and absence of Vif. Because we identified a high frequency of G to A mutations in viral cDNAs, this antiviral activity was mediated by DNA editing. Interestingly, our fusion protein did not restrict murine leukemia virus, which does not incorporate Vpr. Thus, by targeting appropriately a potent single domain cytidine deaminase, we rendered HIV and simian immunodeficiency virus restriction resistant to Vif.

Received for publication, August 3, 2007 , and in revised form, December 5, 2007.

^* This work was supported by research grants from the National Institutes of Health (to B. M. P). 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.

¹ Supported by a fellowship from California HIV/AIDS Research Program.

² To whom correspondence should be addressed: UCSF 533, Parnassus Ave. U422 San Francisco, CA 94143-0703. Tel.: 415-502-1902; Fax: 415-502-1901; E-mail: matija.peterlin{at}ucsf.edu.

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