Dr. Engelman focuses on the mechanism of human immunodeficiency virus type 1 (HIV-1) integration, an essential step in the viral lifecycle. Retroviruses encode their own integrase protein, and Dr. Engelman's research borrows form numerous disciplines including molecular virology and structural biology to understand mechanistic details of integrase function. Integrase active site inhibitors have been in the clinic since 2007, but until recently their mode of action was largely speculative. Novel X-ray crystal structures of the related spumavirus integrase with its DNA substrate yielded unprecedented details of the structural basis of retroviral DNA integration and moreover established how the inhibitors work. Lentiviruses like HIV-1 preferentially target active genes during integration, and Dr. Engelman`s research established that an interaction between integrase and the cellular chromatin binding protein lens epithelium-derived growth factor (LEDGF) plays a significant role in HIV integration targeting. Because X-ray crystal structures pinpointed the LEDGF binding face distal from the integrase active site, small molecule inhibitors of the LEDGF-integrase interaction should afford a novel way to block HIV-1 replication in cells.