Dr. Engelman’s research focuses on the structure and function of human immunodeficiency virus 1 (HIV-1) integrase, which is a high-value antiretroviral drug target. Projects include mechanisms of action of clinical integrase strand transfer inhibitors (INSTIs) as well as the development of inhibitors that work through novel mechanisms of action. Integration of viral DNA into human chromosomal DNA during HIV-1 infection is mediated by the intasome complex, which is composed of a multimer of the integrase protein bound to the ends of linear viral DNA. Structures of INSTIs bound to retroviral intasomes helped to explain that the drugs work by restructuring the viral DNA end, which serves as the scissor to cut human DNA during integration, within the intasome complex. Newer structures with primate lentiviral intasome complexes has additionally helped to explain mechanisms of clinical INSTI resistance. Dr. Engelman studies interactions between HIV-1 integrase and host factors to uncover new ways to inhibit virus infection. Retroviral integration into chromosomal DNA is nonrandom, and lentiviruses such as HIV-1 preferentially integrate into active genes. Dr. Engelman’s research established that the interaction between integrase and cellular chromatin protein lens epithelium-derived growth factor (LEDGF) plays a significant role in HIV integration targeting. Small molecule allosteric integrase inhibitors (ALLINIs) that can inhibit the binding of integrase to LEDGF are potent antivirals, though their mechanisms of action are largely independent of this biochemical activity. ALLINI binding results in aberrant integrase multimerization in a LEDGF-independent manner, leading to the inhibition of virus particle maturation in HIV-1-infected cells. This line of research established that the targeting of integrase with novel small molecule drugs can inhibit HIV-1 infection in a highly unexpected way that is completely separate from the step of viral DNA integration.
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Principal Investigator: Alan N. Engelman, Ph.D.