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J. Biol. Chem., Vol. 280, Issue 10, 8765-8775, March 11, 2005

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HIV-1 Vif Can Directly Inhibit Apolipoprotein B mRNA-editing Enzyme Catalytic Polypeptide-like 3G-mediated Cytidine Deamination by Using a Single Amino Acid Interaction and Without Protein Degradation^*

Mariana Santa-Marta, Frederico Aires da Silva, Ana Margarida Fonseca, and Joao Goncalves¶

From the Unidade de Retrovirus e Infecçôes Associadas, Centro de Patogénese Molecular, Faculdade de Farmácia, Universidade de Lisboa, Av. das Forças Armadas, 1649-019 Lisboa, Portugal

The human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G), also known as CEM-15, is a host-cell factor involved in innate resistance to retroviral infection. HIV-1 viral infectivity factor (Vif) protein was shown to protect the virus from APOBEC3G-mediated viral cDNA hypermutation. The mechanism proposed for protection of the virus by HIV-1 Vif is mediated by APOBEC3G degradation through ubiquitination and the proteasomal pathway. Here we show that in Escherichia coli the APOBEC3G-induced cytidine deamination is inhibited by expression of Vif without depletion of deaminase. Moreover, inhibition of deaminase-mediated bacterial hypermutation is dependent on a single amino acid substitution D128K that renders APOBEC3G resistant to Vif inhibition. This single amino acid was elegantly proven by other authors to determine species-specific sensitivity. Our results show that in bacteria this single amino acid substitution controls Vif-dependent blocking of APOBEC3G that is dependent on a strong protein interaction. The C-terminal region of Vif is responsible for this strong protein-protein interaction. In conclusion, our experiments suggest a complement to the model of Vif-induced degradation of APOBEC3G by bringing to relevance that deaminase inhibition can also result from a direct interaction with Vif protein.

Received for publication, August 13, 2004 , and in revised form, December 17, 2004.

^* This work was supported in part by the Fundação para a Ciência e Tecnologia, Portugal (Grants POCTI/33096/MGI/2000 and PSIDA/MGI/49729/2003). 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.

Recipients of a doctoral fellowship from Fundação para a Ciência e Tecnologia, Portugal.

Supported with a Bolsa de Investigação from Fundação para a Ciência e Tecnologia.

^¶ To whom correspondence should be addressed. Tel.: 351-21-7946489; Fax: 351-21-7946491; E-mail: joao.goncalves{at}ff.ul.pt.

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