Abstract
The HIV-1 integrase enzyme is essential for integrating the viral DNA into the host chromosome. Infection is aborted in the absence of integration, making integrase an attractive antiviral target. Recently approved inhibitors of integrase bind tightly to integrase assembled in a nucleoprotein complex with the viral DNA ends (intasome), but have only low affinity for free integrase. High-resolution structures of HIV-1 intasomes are therefore required to understand the detailed mechanisms of inhibition and resistance. Although the structure of the HIV-1 intasome has not yet been determined, the structure of the related prototype foamy virus (PFV) intasome was recently solved. A new study [1] exploits the PFV structure to model the HIV-1 intasome. The model provides the most reliable picture to date of the active site region of the HIV-1 intasome and is an important advance in studies of inhibition of this essential HIV-1 enzyme.
Highlights
The HIV-1 integrase enzyme is essential for integrating the viral DNA into the host chromosome
Integrase normally functions as part of the preintegration complex (PIC), but integrase alone is able to carry out the key DNA cutting and joining steps in vitro with simple DNA substrates that mimic the viral DNA ends in the presence of a divalent metal ion
In the case of HIV-1, the sites of integration on the two target DNA strands are separated by five nucleotides resulting in a five base pair duplication of target DNA sequence flanking the integrated viral DNA after repair of the resulting integration intermediate by cellular enzymes
Summary
The HIV-1 integrase enzyme is essential for integrating the viral DNA into the host chromosome. DNA strand transfer, the 3' hydroxyls of the terminal adenosine exposed by 3' end processing attack a pair of phosphodiester bonds at the site of integration into target DNA. A key nucleoprotein intermediate is the intasome, comprised of a tetramer of integrase that stably bridges a pair of viral DNA ends [3].
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