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J. Biol. Chem., Vol. 282, Issue 18, 13456-13467, May 4, 2007

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Interaction of Human Immunodeficiency Virus Type 1 Integrase with Cellular Nuclear Import Receptor Importin 7 and Its Impact on Viral Replication^*

Zhujun Ao¹, Guanyou Huang¹, Han Yao, Zaikun Xu, Meaghan Labine², Alan W. Cochrane^¶, and Xiaojian Yao³

From the Laboratory of Molecular Human Retrovirology, Department of Medical Microbiology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, R3E 0W3, the Département de Microbiologie et immunologie, Université de Montréal, Montréal, Québec H3G 1J4, and the ^¶Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Similar to all other viruses, human immunodeficiency virus type 1 (HIV-1) depends heavily on cellular factors for its successful replication. In this study we have investigated the interaction of HIV-1 integrase (IN) with several host nuclear import factors using co-immunoprecipitation assays. Our results indicate that IN interacts specifically with host importin 7 (Imp7) in vivo, but does not interact with importin 8 (Imp8) or importin (Rch1). In contrast, another HIV-1 karyophilic protein MAp17, which is capable of binding Rch1, fails to interact with Imp7, suggesting that IN and Map17 may interact with different cellular pathways during HIV-1 replication. Genetic analysis revealed that the C-terminal domain of IN is the region responsible for interaction between IN with Imp7, and an IN mutant (K240A,K244A/R263A,K264A) disrupted the Imp7 binding ability of the protein, indicating that both regions (²³⁵WKGPAKLLWKG and ²⁶²RRKAK) within the C-terminal domain of IN are required for efficient IN/Imp7 interaction. Using a vesicular stomatitis virus G glycoprotein pseudotyped HIV single-cycle replication system, we showed that the IN/Imp7 interaction-deficient mutant was unable to mediate viral replication and displayed impairment at both viral reverse transcription and nuclear import steps. Moreover, transient knockdown of Imp7 in both HIV-1 producing and target cells resulted in a 2.5–3.5-fold inhibition of HIV infection. Altogether, our results indicate that HIV-1 IN specifically interacts with Imp7, and this viral/cellular protein interaction contributes to efficient HIV-1 infection.

Received for publication, November 13, 2006 , and in revised form, March 12, 2007.

^* This work was supported in part by Canadian Institutes of Health Research Grants HOP-63013 and HOP 81180 (to X. J. Y.). 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 Both authors contributed equally to this work.

² Recipient of studentship from Health Sciences Center (HSC) Foundation.

³ Recipient of the Basic Science Career Development Research Award from Manitoba Medical Service Foundation. To whom correspondence should be addressed. Tel.: 204-977-5677; Fax: 204-789-3926; E-mail: yao2{at}cc.umanitoba.ca.

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