Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that enables its genetic material to be integrated into the DNA of the infected cell. Retroviral INs are not to be confused with phage integrases, such as λ phage integrase (Int) (see site-specific recombination).
IN is a key component in the retroviral pre-integration complex (PIC).
All retroviral IN proteins contain three canonical domains, connected by flexible linkers:
- an N-terminal HH-CC zinc-binding domain (a three-helical bundle stabilised by coordination of a Zn(II) cation)
- a catalytic core domain (RNaseH fold)
- a C-terminal domain (SH3 fold)
Biochemical data and structural data suggest that retroviral IN functions as a tetramer (dimer-of-dimers). All three domains are important for multimerisation and viral DNA binding. Early in 2010, scientists announced that they had grown a crystal allowing detailed analysis of the structure of IN from prototype foamy virus (PFV) assembled on viral DNA ends.
In addition, several host cellular proteins have been shown to interact with IN to facilitate the integration process. Human chromatin-associated protein LEDGF, which tightly binds HIV IN and directs HIV PIC towards highly-expressed genes for integration, is an example of such a host factor.
Integration occurs following production of the double-stranded 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, a step that is essential for HIV replication. Integration is a point of no return for the cell, which becomes a permanent carrier of the viral genome (provirus). Integration is in part responsible for the persistence of retroviral infections. After integration, the viral gene expression and particle production may take place immediately or at some point in the future. The timing presumably depends on the activity of the chromosomal locus hosting the provirus.
Retroviral IN catalyzes two reactions:
- 3'-processing, in which two or three nucleotides are removed from one or both 3' ends of the viral DNA to expose the invariant CA dinucleotides at both 3'-ends of the viral DNA.
- the strand transfer reaction, in which the processed 3' ends of the viral DNA are covalently ligated to the host chromosomal DNA.
Importantly, both reactions are catalysed by the same active site and occur via transesterification, without a covalent protein-DNA intermediate, in contrast to reactions catalysed by Ser and Tyr recombinases (see site specific recombination).
HIV integrase is a 32 kDa protein produced from the C-terminal portion of the Pol gene product, and is an attractive target for new anti-HIV drugs.
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