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Molecular mechanisms of HIV integration and therapeutic intervention

Retroviruses, such as human immunodeficiency virus type 1 (HIV-1), are plus-sense RNA viruses that require reverse transcription and then DNA integration to establish a chromosomal provirus as an obligate replication intermediate. The viral enzyme reverse transcriptase synthesises linear double-stranded cDNA, which is the template for the viral enzyme integrase. Integrase catalyses two separate chemical reactions: an initial 3′ processing of the nascent cDNA ends, which is followed in the cell nucleus by their covalent attachment to the 5′ phosphates of a double-stranded staggered cut in chromosomal DNA. As integrase activity is essential for productive retroviral infection, there is intense interest in developing small-molecule inhibitors of the HIV-1 enzyme to increase the breadth of the antiviral arsenal used to fight HIV/AIDS. Purified integrase protein displays the 3′ processing and DNA-strand-transfer activities essential for cDNA integration in integration assays in vitro, but numerous studies indicate that cellular proteins play important roles during integration in infected cells. This review highlights the molecular mechanisms behind HIV-1 integration, focusing on recent insights into functions of human cellular cofactors. The progress towards developing integrase inhibitors for their use in the clinic is also reviewed.