Integrase

Integrase is an enzyme produced by a retrovirus (including HIV) that enables its genetic material to be integrated into the DNA of the infected cell. It is also produced by viruses containing double stranded DNAs for the same purpose.

It is a key component in the pre-integration complex (PIC).

tructure

The integrase protein contains three domains:
* an N-terminal HH-CC zinc finger domain believed to be partially responsible for multimerization,
* a central catalytic domain
* a C-terminal.

Both the Central catalytic domain and C-terminal domains have been shown to bind both viral and cellular DNA. Currently no crystal structure data exists with Integrase bound to its DNA substrates.

Biochemical data and structural data suggest that integrase functions as a dimer or a tetramer.

Additionally, several host cellular proteins have been shown to interact with integrase and may facilitate the integration process.

Function

Integration occurs following production of the double-stranded viral DNA by the viral DNA polymerase, reverse transcriptase.

Integrase acts to insert the proviral DNA into the host chromosomal DNA, a step which is essential for HIV replication.

Integrase catalyzes two reactions;
* 3'-end processing, in which two deoxynucleotides are removed from the 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.

Integration of the proviral DNA is essential for the subsequent transcription of the viral genome which leads to production of new viral genomic RNA and viral proteins needed for the production of the next round of infectious virus.

Essentially, integrase is a key step in allowing viral DNA to become a permanent member of the host genome. This integrated proviral DNA is then translated using host cell machinery (see translation) into viral proteins.

HIV integrase

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.

In November 2005, data from a phase 2 study of an investigational HIV integrase inhibitor, MK-0518, demonstrated that the compound had potent antiviral activity. [Morales-Ramirez JO, Teppler H, Kovacs C, et al. Antiretroviral effect of MK-0518, a novel HIV-1 integrase inhibitor, in ART-naïve HIV-1 infected patients. Program and abstracts of the 10th European AIDS Conference; November 17-20, 2005; Dublin, Ireland. Abstract LBPS1/6. Online summary: http://clinicaloptions.com/HIV/Conference%20Coverage/Dublin%202005/Capsules/LBPS1-6.aspx] [Savarino A. A historical sketch of the discovery and development of HIV-1 integrase inhibitors. Expert Opin Investig Drugs. 2006 Dec;15(12):1507-22. ] On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor Raltegravir (MK-0518, brand name IsentressTM). [ [http://www.cnn.com/2007/HEALTH/10/12/hiv.drug/index.html#cnnSTCText FDA approves drug that fights HIV in new way - CNN.com ] ] As of April 2008, this is the only integrase inhibitor approved for treating HIV Infection.

External links

*
*http://discover.nci.nih.gov/pommier/IntegraseBookFull.pdf

References