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HIV-1 integrase is a critical enzymatic molecule for viral DNA integration.In addition,this viral protein has also been shown to play important roles in other steps during viral replication,including viral DNA nuclear import.Although the karyophilic property ofintegrase has been well demonstrated,how this protein contributes to HIV-l DNA nuclear import is still not fully understood.In this study,we have explored the molecular mechanisms underlying its action during HIV-1 replication and demonstrated that HIV-1 IN,but not for HIV-1 matrix p 17 protein,specifically interacts with one of cellular nuclear import receptors.Also,our in vitro analysis indicates that this viral/cellular complex may be through a direct protein/protein interaction and the receptor-binding site in HIV-1 integrase was identified in the C-terminal domain of the protein.In attempt to elucidate the functional role of this viral/cellular protein interaction,our mutagenic and siRNA lockdown analyses revealed that this viral/cellular protein interaction is indeed necessary for an efficient HIV-1 replication.All of these studies suggest that IN may utilize an unique cellular nuclear transport pathway and contribute to HIV-1 replication and further studies of molecular mechanisms of this viral/cellular protein interactions during HIV-1 replication may lead to the development of innovative therapeutic strategies against HIV-1 infection.