Integrase

Early in the HIV lifecycle, reverse transcription of viral RNA generates a double-stranded DNA copy of the RNA genome with long terminal repeats at the ends. HIV-1 Integrase (IN) is the viral enzyme that forms a large pre-integration complex (PIC) between this newly synthesized viral genome and cellular proteins in order to insert the viral DNA into the host genome. Several proteins have been identified in functional PICs. These include INI1, BAF, HMGA1 and LEDGF/p75.

The goal of the Integrase project, headed by Dr. Robert M. Stroud, is to understand the mechanism of HIV-1 integration mediated by integrase, including its interactions with protein partners in the context of PICs that provide targets for anti-IN drugs. This research builds on Dr. Stroud's previously determined structures of the isolated core domain of integrase (IN^52-210) and the two domain catalytic core plus C-terminal domain (IN^52-288). These structures diffract to 1.6 and 2.8 Å, respectively, and represent the highest resolution cores of HIV-1 IN solved to date. The HARC Center IN project utilizes x-ray diffraction and cryo-EM and tomography to determine structures of integrase complexed with nucleic acid and protein partners. Ultimately, such studies will define the molecular binding sites for known small molecule inhibitors of IN, by combining the experimental structures with computational methods.