Molecule of the Month: Integrase

Retroviruses, such as HIV, are particularly insidious. Most viruses infect a cell, force it make many new copies of the virus, and then leave when the cell is used up. Retroviruses, however, take a long-term approach to infection. They enter cells and build a DNA copy of their genome. Then, they insert this viral genome into the cell's own DNA. This integrated DNA can be used immediately to build more viruses, or it can stay dormant, waiting for the best time to start virus production. This is one of the many reasons that HIV is so hard to fight: it can lie waiting in these long-lived cells for years.

Integrase is the enzyme that splices the viral DNA into a cellular chromosome. Four identical copies of integrase grab the two ends of the viral DNA, creating a stable complex called an intasome. The intasome then binds to the cellular DNA and performs a strand transfer reaction, joining the viral DNA to the cellular DNA. The structure shown here (PDB entry 3os1 ) includes four integrase subunits (in blue) and three short pieces of DNA that correspond to the two viral DNA ends (red) and the cellular DNA (orange). The two integrase subunits at the center (light blue) provide the active sites that cut and join the DNA, and the outer pair of integrate subunits (dark blue) play a structural role.

Researchers have been studying HIV integrase for years, trying to understand how it works so that they can design drugs to fight AIDS. This work has led to the development of several effective drugs, including raltegravir, which is currently being used to treat HIV infection. So far, it has proven difficult to crystallize full-length HIV integrase and its complexes with DNA. The structures shown here are from a related retrovirus, prototype foamy virus (PFV). Although PFV is harmless, it is very similar to HIV integrase and provides an excellent model for studies of retroviral integration.