Kelly Lee

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

Taking Students: Yes

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 (Pharmaceutics) 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.

Recent Publications

PubMed Link

• Prebiotic amino acids bind to and stabilize prebiotic fatty acid membranes. Cornell CE, Black RA, Xue M, Litz HE, Ramsay A, Gordon M, Mileant A, Cohen ZR, Williams JA, Lee KK, Drobny GP, Keller SL. Proc Natl Acad Sci U S A. 2019 Aug 12. pii: 201900275. doi: 10.1073/pnas.1900275116. [Epub ahead of print]
• Deep Mutational Scan of the Highly Conserved Influenza A Virus M1 Matrix Protein Reveals Substantial Intrinsic Mutational Tolerance. Hom N, Gentles L, Bloom JD, Lee KK. J Virol. 2019 Jun 14;93(13). pii: e00161-19. doi: 10.1128/JVI.00161-19. Print 2019 Jul 1.
• De novo design of tunable, pH-driven conformational changes. Boyken SE, Benhaim MA, Busch F, Jia M, Bick MJ, Choi H, Klima JC, Chen Z, Walkey C, Mileant A, Sahasrabuddhe A, Wei KY, Hodge EA, Byron S, Quijano-Rubio A, Sankaran B, King NP, Lippincott-Schwartz J, Wysocki VH, Lee KK, Baker D. Science. 2019 May 17;364(6441):658-664. doi: 10.1126/science.aav7897.
• Kappa chain maturation helps drive rapid development of an infant HIV-1 broadly neutralizing antibody lineage. Simonich CA, Doepker L, Ralph D, Williams JA, Dhar A, Yaffe Z, Gentles L, Small CT, Oliver B, Vigdorovich V, Mangala Prasad V, Nduati R, Sather DN, Lee KK, Matsen Iv FA, Overbaugh J. Nat Commun. 2019 May 16;10(1):2190. doi: 10.1038/s41467-019-09481-7.
• Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus. Marcandalli J, Fiala B, Ols S, Perotti M, de van der Schueren W, Snijder J, Hodge E, Benhaim M, Ravichandran R, Carter L, Sheffler W, Brunner L, Lawrenz M, Dubois P, Lanzavecchia A, Sallusto F, Lee KK, Veesler D, Correnti CE, Stewart LJ, Baker D, Loré K, Perez L, King NP. Cell. 2019 Mar 7;176(6):1420-1431.e17. doi: 10.1016/j.cell.2019.01.046.
• Tracking Higher Order Protein Structure by Hydrogen-Deuterium Exchange Mass Spectrometry. Benhaim M, Lee KK, Guttman M. Protein Pept Lett. 2019;26(1):16-26. doi: 10.2174/0929866526666181212165037. Review.
• Influenza Virus-Liposome Fusion Studies Using Fluorescence Dequenching and Cryo-electron Tomography. Gui L, Lee KK. Methods Mol Biol. 2018;1836:261-279. doi: 10.1007/978-1-4939-8678-1_13.
• Single-Molecule Analysis of a Viral Fusion Protein Illuminates a Fusion-Active Intermediate State. Benhaim M, Lee KK. Cell. 2018 Aug 9;174(4):775-777. doi: 10.1016/j.cell.2018.07.026.
• Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. Pardi N, Hogan MJ, Naradikian MS, Parkhouse K, Cain DW, Jones L, Moody MA, Verkerke HP, Myles A, Willis E, LaBranche CC, Montefiori DC, Lobby JL, Saunders KO, Liao HX, Korber BT, Sutherland LL, Scearce RM, Hraber PT, Tombácz I, Muramatsu H, Ni H, Balikov DA, Li C, Mui BL, Tam YK, Krammer F, Karikó K, Polacino P, Eisenlohr LC, Madden TD, Hope MJ, Lewis MG, Lee KK, Hu SL, Hensley SE, Cancro MP, Haynes BF, Weissman D. J Exp Med. 2018 Jun 4;215(6):1571-1588. doi: 10.1084/jem.20171450. Epub 2018 May 8.
• Superinfection Drives HIV Neutralizing Antibody Responses from Several B Cell Lineages that Contribute to a Polyclonal Repertoire. Williams KL, Wang B, Arenz D, Williams JA, Dingens AS, Cortez V, Simonich CA, Rainwater S, Lehman DA, Lee KK, Overbaugh J. Cell Rep. 2018 Apr 17;23(3):682-691. doi: 10.1016/j.celrep.2018.03.082.
• Probing Structural Variation and Dynamics in the HIV-1 Env Fusion Glycoprotein. Munro JB, Lee KK. Curr HIV Res. 2018;16(1):5-12. doi: 10.2174/1570162X16666171222110025. Review.
• Dissection of Epitope-Specific Mechanisms of Neutralization of Influenza Virus by Intact IgG and Fab Fragments. Williams JA, Gui L, Hom N, Mileant A, Lee KK. J Virol. 2018 Feb 26;92(6). pii: e02006-17. doi: 10.1128/JVI.02006-17. Print 2018 Mar 15.
• Improving the Immunogenicity of Native-like HIV-1 Envelope Trimers by Hyperstabilization. Torrents de la Peña A, Julien JP, de Taeye SW, Garces F, Guttman M, Ozorowski G, Pritchard LK, Behrens AJ, Go EP, Burger JA, Schermer EE, Sliepen K, Ketas TJ, Pugach P, Yasmeen A, Cottrell CA, Torres JL, Vavourakis CD, van Gils MJ, LaBranche C, Montefiori DC, Desaire H, Crispin M, Klasse PJ, Lee KK, Moore JP, Ward AB, Wilson IA, Sanders RW. Cell Rep. 2017 Aug 22;20(8):1805-1817. doi: 10.1016/j.celrep.2017.07.077.
• Extracellular Matrix Proteins Mediate HIV-1 gp120 Interactions with α₄β₇. Plotnik D, Guo W, Cleveland B, von Haller P, Eng JK, Guttman M, Lee KK, Arthos J, Hu SL. J Virol. 2017 Oct 13;91(21). pii: e01005-17. doi: 10.1128/JVI.01005-17. Print 2017 Nov 1.