Kelly Lee

Associate Professor

Department of Medicinal Chemistry, Medicinal Chemistry Faculty

Expertise: HIV and AIDS, Infectious Diseases, Mass Spectrometry, Vaccines and Virology

Telephone: (206) 616-3972

Email: kklee@uw.edu

Website: Lab website

Education

  • AB (Honors), Harvard University
  • PhD, Johns Hopkins University

Research Interests

  • HIV, Influenza A virus
  • Biophysical, structural, and biochemical techniques including X-ray scattering, cryo-electron microscopy, hydrogen/deuterium-exchange mass spectrometry, and fluorescence microscopy to understand the function of viral machinery

Biography

Our lab uses complementary structural and biophysical methods to characterize the conformational changes viruses carry out in order to invade host cells. We focus on the transitions and the critical functional states that often are too transient or dynamic to characterize by classical structural methods. Understanding these events is essential to understanding mechanisms of cell entry, for understanding the activity of neutralizing antibodies, and also for developing novel antivirals that can target the virus prior to infection. Our core expertise is in using Hydrogen/Deuterium-Exchange Mass Spectrometry (HDX-MS), cryo-electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) to monitor conformational change of protein complexes and viruses. An NIH K99/R00 Career Award supported my transition to studying influenza virus with techniques such as cryo-electron tomography and SAXS. Current projects apply cryo-ET, SAXS, and HDX-MS to dissect the spring-loaded membrane fusion mechanism of influenza virus hemagglutinin (HA) and HIV Env.

For example, in recent studies using cryo-ET and HDX-MS, for the first time we have been able to visualize the nature of fusion protein-mediated membrane remodeling and to determine the sequence of events in whole viruses and isolated fusion proteins that are needed to produce efficient fusion.

With the support of a Center for AIDS Research Creative and Novel Ideas in HIV Research (CNIHR) award for new investigators and with Gates Foundation support, my lab is working with Shiu-Lok Hu’s group (Pharmaceutcs) to investigate the structural basis for antigenicity and immunogenicity of HIV Env glycoproteins. In addition, we have been able to characterize isolate-specific structural differences and their impact on antigenicity of Env; these effects are difficult to study by conventional approaches. Our biophysical approaches have also enabled us to analyze CD4 receptor, entry inhibitors, and neutralizing Abs in complex with the native-like HIV Env trimers. In collaboration with Julie Overbaugh’s group at the Fred Hutchinson Cancer Research Center, we are gaining insight into the nature of Env-dependent HIV transmission and the development of neutralizing antibodies in response to infection.

Dr. Lee also holds an adjunct appointment in the UW Microbiology Department and is a member of a number of cross-departmental graduate programs including the Biological Physics Structure and Design Program, the Pathobiology Graduate Program and the Molecular and Cellular Biology Program.

Selected Publications

PubMed Link

  • Strauch EM, Bernard SM, La D, Bohn AJ, Lee PS, Anderson CE, Nieusma T, Holstein CA, Garcia NK, Hooper KA, Ravichandran R, Nelson JW, Sheffler W, Bloom JD, Lee KK, Ward AB, Yager P, Fuller DH, Wilson IA, Baker D. “Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site.” Nat Biotechnol. 2017 Jun 12. PubMed link. [Epub ahead of print]
  • Klasse PJ, LaBranche CC, Ketas TJ, Ozorowski G, Cupo A, Pugach P, Ringe RP, Golabek M, van Gils MJ, Guttman M, Lee KK, Wilson IA, Butera ST, Ward AB, Montefiori DC, Sanders RW, Moore JP. “Sequential and Simultaneous Immunization of Rabbits with HIV-1 Envelope Glycoprotein SOSIP.664 Trimers from Clades A, B and C.” PLoS Pathog. 2016 Sep 14;12(9):e1005864. PubMed link.
  • Verkerke HP, Williams JA, Guttman M, Simonich CA, Liang Y, Filipavicius M, Hu SL, Overbaugh J, Lee KK. “Epitope-Independent Purification of Native-Like Envelope Trimers from Diverse HIV-1 Isolates.” J Virol. 2016 Sep 29;90(20):9471-82. PubMed link.
  • Liang Y, Guttman M, Williams JA, Verkerke H, Alvarado D, Hu SL, Lee KK. “Changes in Structure and Antigenicity of HIV-1 Env Trimers Resulting from Removal of a Conserved CD4 Binding Site-Proximal Glycan.” J Virol. 2016 Sep 29;90(20):9224-36. PubMed link.
  • Joyce MG, Zhang B, Ou L, Chen M, Chuang GY, Druz A, Kong WP, Lai YT, Rundlet EJ, Tsybovsky Y, Yang Y, Georgiev IS, Guttman M, Lees CR, Pancera M, Sastry M, Soto C, Stewart-Jones GB, Thomas PV, Van Galen JG, Baxa U, Lee KK, Mascola JR, Graham BS, Kwong PD. “Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV.” Nat Struct Mol Biol. 2016 Sep;23(9):811-20. PubMed link.
  • Gui L, Ebner JL, Mileant A, Williams JA, Lee KK. “Visualization and Sequencing of Membrane Remodeling Leading to Influenza Virus Membrane Fusion.”Journal of Virology. 2016 Jul 11;90(15):6948-62.  PubMed link.
  • Simonich C, Williams KL, Verkerke HP, Williams JA, Nduati R, Lee KK, Overbaugh J. “HIV-1 Neutralizing Antibodies with Limited Hypermutation from an Infant.” Cell. 2016 Jun 30;166(1):77-87. PubMed link.
  • Lee KK, Gui L. “Dissecting Virus Infectious Cycles by Cryo-electron Microscopy.”PLoS Pathogens. 2016.[in press].
  • Liang Y, Davenport TM, Guttman M, Hu SL, Lee KK, “Probing the Impact of Local Structural Dynamics of conformational epitopes on Antibody Recognition.”Biochiemistry. 2016 Apr 19;55(15)197-213. PubMed link.
  • Garcia NK, Lee KK, “Dynamic Viral Glycoprotein Machines: Approaches for Probing Transient States that Drive Membrane Fusion.”Viruses. 2016 Jan 11;8(1):15. PubMed link.
  • De Taeye SW, Ozorowski G, Torrents de la Peí±a A, Guttman M, Julient JP, van den Kerkhof TL, Burger JA, Pritchard LK, Pugach P, Yasmeen A, Crampton J, Hu J, Bontjer I, Torres JL, Arendt H, DeStefano J, Koff WC, Schuitemaker H, Eggink D, Berkhout B, Dean H, LaBranche C, Crotty S, Crispin M, Montefiori DC, Classe PJ,Lee KK, Moore JP, WIlson IA, Ward Ab, Sanders RW. “Immunogenicity of Stabilized HIV-Env Trimers with Reduced Exposure of Non-neutralized Epitopes.”Cell. 2015 Dec 17;163(7):1702-1715. PubMed link.
  • Gupta S, Guttman M, Leverenz RL, Zhumadilova K, Pawlowski EG, Petzold CJ,Lee KK, Ralston C, Kerfeld CA. “Local and Global Structural Drivers for the Photoactivation of the Orange Carotenoid Protein.”Proceedings of the National Academy of Sciences. 2015 Oct 13;112(41):E5567-5574. PubMed link.
  • Kwon YD, Pancera M, Acharya P, Georgiev IS, Crooks ET, Gorman J, Joyce MG, Guttman M, Ma X, Nrpoala S, Soto C, Terry DS, Yang Y, Zhou T, Ahlsen G, Bailer RT, Chambers M, Chuang GY, Doria-Rose NA, Druz A, Hallen MA, Harned A, Kirys T, Louder MK, O\’Dell S, Ofek G, Osawa K, Prabhakaran M, Sastry M, Stewart-Jones GB, Stuckey J, Thomas PV, Tittley T, Williams C, Zhang B, Zhao H, Zou Z, Donald BR, Lee LK, Zolla-Pazner S, Baxa U, Schí_n A, Freire E, Shapiro L,Lee KK, Arthos J, Munro JB, Blanchard SC, Mothes W, Binley JM, McDermott AB, Mascola JR,Kwong PD. “Crystal Structure Conformational Fixation and Entry-Related Interactions of Mature Ligand-free HIV-1 Env.” Nature Structural and Molecular Biology. 2015 July;22(7):22-531. PubMed link.
  • Garcia NK, Guttman M, Ebner JL,Lee KK. “Dynamic Changes during Acid-Induced Activation of Influenza Hemagglutinin.”Structure2015 Apr 7; 23(4):665-76.PubMed link.
  • Gui L, Jurgens E, Ebner JL, Porotto M, Moscona A,Lee KK. “Electron Tomography Imaging of Surface Glycoproteins on Human Parainfluenza Virus 3: Association of Receptor Binding and Fusion Proteins Before Receptor Engagement.”mBio. 2015 Feb 17;6(1):e02393-14.PubMed link.
  • Guttman M, Cupo A, Julien JP, Sanders RW, Wilson IA, Moore JP,Lee KK. “Antibody potency relates to the ability to recognize the closed, pre-fusion form of HIV Env.”Nature Communications.2015 Feb 5; 6:6144.PubMed link.
  • Guttman M, Garcia NK, Cupo A, Matsui T, Julien JP, Sanders RW, Wilson IA, Moore JP,Lee KK. “CD4-induced activation in a soluble HIV-1 Env trimer.”Structure.2014 Jul 8; 22(7):974-84.PubMed link.
  • Davenport TM, Guttman M, Guo W, Cleveland B, Kahn M, Hu SL,Lee KK. “Isolate-specific Differences in the Conformational Dynamics and Antigenicity of HIV-1 gp120.” Journal of Virology.2013 Oct;87(19):10855-10873.PubMed link.
  • Guttman M, Kahn M, Garcia NK, Hu S-L, Lee KK. “Solution Structure, Conformational Dynamics, and CD4-induced Activation in Full-length, Glycosylated, Monomeric HIV gp120.” Journal of Virology 2012; 86(16):8750-64.PubMed link.
  • Lee KK.“Architecture of a Nascent Viral Fusion Pore.” The EMBO Journal. 2010 Apr 7;29(7):1299-1311.PubMed link.