Modeling the HIV-1 Intasome: A Prototype View of the Target of Integrase Inhibitors

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.