Integrase

Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates (forms covalent links between) its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage integrases (recombinases) used in biotechnology, such as λ phage integrase, as discussed in site-specific recombination. The macromolecular complex of an IN macromolecule bound to the ends of the viral DNA ends has been referred to as the intasome; IN is a key component in this and the retroviral pre-integration complex. All retroviral IN proteins contain three canonical domains, connected by flexible linkers: ● an N-terminal HH-CC zinc-binding domain (a three-helical bundle stabilized by coordination of a Zn(II) cation) ● a catalytic core domain (RNaseH fold) ● a C-terminal DNA-binding domain (SH3 fold). Crystal and NMR structures of the individual domains and 2-domain constructs of integrases from HIV-1, HIV-2, SIV, and Rous Sarcoma Virus (RSV) have been reported, with the first structures determined in 1994. Biochemical data and structural data suggest that retroviral IN functions as a tetramer (dimer-of-dimers), with all three domains being important for multimerization and viral DNA binding. In addition, several host cellular proteins have been shown to interact with IN to facilitate the integration process: e.g., the host factor, human chromatin-associated protein LEDGF, tightly binds HIV IN and directs the HIV pre-integration complex towards highly expressed genes for integration. Human foamy virus (HFV), an agent harmless to humans, has an integrase similar to HIV IN and is therefore a model of HIV IN function; a 2010 crystal structure of the HFV integrase assembled on viral DNA ends has been determined. Integration occurs following production of the double-stranded linear viral DNA by the viral RNA/DNA-dependent DNA polymerase reverse transcriptase. The main function of IN is to insert the viral DNA into the host chromosomal DNA, an essential step for HIV replication.