Seeing is believing: Structure of the catalytic domain of HIV-1 integrase in complex with human LEDGF/p75

Retroviruses covalently insert their genome into the DNA of the host cell and subsequently coopt cellular machinery for DNA replication, transcription, and protein expression (1). These viruses also exploit cellular proteins to assist in this stable insertion of their genetic material into the host genome, a process called integration. In a recent issue of PNAS, Cherepanov et al. (2) reported the first structure of a retroviral integrase, the viral enzyme that catalyzes integration, in complex with a host protein. This definitive structural evidence for an interaction between HIV-1 integrase and any other protein adds to the significant evidence for the role of host proteins in integration that has been accumulated over the past decade (ref. 3 and references therein).

The infectious particles of retroviruses, called virions, contain two RNA copies of their genomes. After viral entry and a series of poorly understood uncoating steps, the RNA is released into the host cytoplasm. Here the viral enzyme reverse transcriptase synthesizes a double-stranded DNA copy of the genome by using the RNA as a template. The next step is the hallmark of the retroviral life cycle: the viral cDNA is transported to the nucleus and is inserted into the host genome (1). Integration is required for infection and ensures the stable association of the viral genome in the host cell for subsequent generations. From its new position, the viral genome is transcribed, leading to the synthesis of viral proteins and full-length transcripts of the genome and, ultimately, to new virus particles.

The chemistry of integration is catalyzed by the viral enzyme integrase, many copies of which are found in the virion (1). The integration reaction has been successfully recapitulated in vitro with recombinant integrase and short DNA oligonucleotides representing the viral DNA ends and the target DNA. With this approach, the biochemical …