• Researcher Profile

    Alan N. Engelman, PhD

     
    Alan N. Engelman, PhD
     
    Associate Professor of Medicine, Harvard Medical School

    Office phone: 617-632-4361
    Fax: 617-632-4338
    Email: alan_engelman@dfci.harvard.edu

    Preferred contact method: office phone
     
     

    Research Department

    Cancer Immunology and AIDS

    Area of Research

    Mechanism of HIV-1 Integration and Preintegration Complex Function

    450 Brookline Avenue
    Center for Life Sciences 1010
    Boston, MA 02215

    Biography

    Dr. Engelman received his PhD in 1990 from Tufts University School of Medicine and his postdoctoral training at the National Institute of Diabetes, Digestive, and Kidney Diseases. He joined DFCI in 1995, where he conducts research on the mechanism of HIV-1 integration and teaches PhD candidates in the graduate program in virology at Harvard Medical School.

    Research

    Mechanism of HIV-1 Integration and Preintegration Complex Function

    Human immunodeficiency virus type 1 (HIV-1) is the causative agent of the AIDS epidemic. As with all viruses, HIV-1 replication proceeds through a series of defined steps. Following infection, the viral enzyme reverse transcriptase copies the viral RNA into double-stranded cDNA. The viral enzyme integrase then integrates this cDNA into a cell chromosome. Because integration is an essential step in the viral lifecycle, research is dedicated to deciphering its molecular details with the goal of developing inhibitors for use in the clinic with AIDS patients.
    HIV-1 integrase enters the infected cell as a part of the virus. Prior to integration, integrase, viral cDNA, and other viral and host cell proteins form an integration-competent nucleoprotein complex known as the preintegration complex. Although work with purified proteins has revealed certain aspects of integrase structure and function, little is known about the detailed structure of the HIV-1 preintegration complex. We described the native protein-DNA structure of the preintegration complex using a sensitive DNA footprinting assay based on polymerase chain reaction (PCR).
    Viruses obviously depend on cells to accomplish their replication, and a relatively new area of HIV-1 research focuses on defining virus-host cell interactions essential for replication. Knowing these interactions might define beneficial targets for drug development, as the host component cannot change its composition as readily as the virus mutates.
    Our group determined that the barrier-to-autointegration factor, which is a normal component of the cell nucleus, plays an important role in HIV-1 integration. More recently, we determined that the cellular transcriptional co-activator lens epithelium-derived growth factor (LEDGF)/p75 was the dominant binding partner of HIV-1 integrase in human cells. We recently solved the three-dimensional structure of the part of LEDGF/p75 that binds to integrase, revealing the first structure of a host cell factor that tightly binds a retroviral enzyme. Generating mice knocked-out for LEDGF/p75 will afford a genetic system for precisely gauging the importance of this host cell factor in HIV-1 replication. Screening libraries of small molecules will help determine whether interfering with the LEDGF/p75-integrase interaction is a viable strategy for antiviral drug development.

    Select Publications

    • Shun MC, Daigle JE, Vandegraaff N, Engelman A. Wild-type levels of human immunodeficiency virus type 1 infectivity in the absence of cellular emerin protein. J Virol 2007; 81:166-72.
    • Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature; in press.
    • Daelemans D, Lu R, De Clercq E, Engelman A. Characterization of a replication-competent, integrase defective human immunodeficiency virus (HIV)/simian virus 40 chimera as a powerful tool for the discovery and validation of HIV integrase inhibitors. J Virol 2007; 81:4381-5.
    • Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev 2007; 21:1767-78.
    • Botbol Y, Raghavendra NK, Rahman S, Engelman A, Lavigne M. Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro. Nucleic Acids Res 2008; 36:1237-46.
    • Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ. Identification of host proteins required for HIV infection through a functional genomic screen. Science 2008; 319:921-6.
    • Shun MC, Botbol Y, Li X, Di Nunzio F, Daigle JE, Yan N, Lieberman J, Lavigne M, Engelman A. Identification and characterization of PWWP domain residues critical for LEDGF/p75 chromatin-binding and human immunodeficiency virus type 1 infectivity. J Virol 2008; 82:11555-67.
    • Hare S, Shun MC, Gupta SS, Valkov E, Engelman A, Cherepanov P. A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75. PLoS Pathog 2009; 5:e1000259.
    • Yan N, Cherepanov P, Daigle JE, Engelman A, Lieberman J. The SET complex acts as a barrier to autointegration of HIV-1. PLoS Pathog 2009; 5:e1000327.
    • Hare S, Di Nunzio F, Labeja A, Wang J, Engelman A, Cherepanov P. Structural basis for functional tetramerization of lentiviral integrase. PLoS Pathog 2009; 5:e1000515.
    • Krishnan L, Matreyek K, Oztop I, Lee K, Tipper CH, Li X, Dar MJ, KewalRamani VK, Engelman A. The requirement for cellular transportin 3 (TNPO3 or TRN-SR2) during infection maps to human immunodeficiency virus type 1 capsid and not integrase. J Virol 2010; 84:397-406.
    • Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov P. Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity. J Biol Chem 2010; 285:541-54.

    Trainees

    • Shun, Ming-Chieh (Michelle), PhD
    • Krishnan, Lavanya, PhD
    • Li, Xiang, PhD
    • Koh, Yasuhiro, MD, PhD
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