Our laboratory focuses on the structural biology of chromatin function and its interactions with retroviral integration machinery.
Retroviral replication requires stable insertion of the viral genetic material into cellular genome. The catalytic events associated with this process are carried out by the virus-derived enzyme integrase (IN). As one of the three essential HIV enzymes, IN is an important target for anti-HIV/AIDS drug development.
On the flip side, the unique ability of retroviruses to efficiently integrate their genetic material into host cell chromosomal DNA makes them ideal tools for gene delivery. In principle, a single application of a retroviral vector may be sufficient to correct a genetic deficiency, make cells resistant to infection or help the immune system to fight off cancer. Yet, uncontrolled integration of retroviral vectors poses an inherent risk of insertional mutagenesis and, consequently, serious side effects.
Over the years, we determined a collection of molecular structures (Figs 1 and 2), which illustrated the mechanism of the retroviral integration process and revealed the mode of action of clinical HIV-1 IN inhibitors, such as Raltegravir. The brunt of our current efforts is directed towards understanding the rules of engagement between the retroviral integration machinery and the cellular environment. We hope that our research will yield the keys to developing safer retroviral vectors as well as novel concepts for anti-retroviral therapies.