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

Visualizing intermediate stages of viral membrane fusion by cryo-electron tomography. Kephart SM, Hom N, Lee KK.Trends Biochem Sci. 2024 Oct;49(10):916-931. doi: 10.1016/j.tibs.2024.06.012. Epub 2024 Jul 24.

Potent neutralization of SARS-CoV-2 variants by RBD nanoparticle and prefusion-stabilized spike immunogens. Miranda MC, Kepl E, Navarro MJ, Chen C, Johnson M, Sprouse KR, Stewart C, Palser A, Valdez A, Pettie D, Sydeman C, Ogohara C, Kraft JC, Pham M, Murphy M, Wrenn S, Fiala B, Ravichandran R, Ellis D, Carter L, Corti D, Kellam P, Lee K, Walls AC, Veesler D, King NP. NPJ Vaccines. 2024 Oct 8;9(1):184.

mRNA-based VP8* nanoparticle vaccines against rotavirus are highly immunogenic in rodents. Roier S, Mangala Prasad V, McNeal MM, Lee KK, Petsch B, Rauch S. NPJ Vaccines. 2023 Dec 22;8(1):190.

Combinatorial immune refocusing within the influenza hemagglutinin RBD improves cross-neutralizing antibody responses Dosey A, Ellis D, Boyoglu-Barnum S, Syeda H, Saunders M, Watson MJ, Kraft JC, Pham MN, Guttman M, Lee KK, Kanekiyo M, King NP. Cell Rep. 2023 Dec 26;42(12):113553.

De novo design of monomeric helical bundles for pH-controlled membrane lysis. Goldbach N, Benna I, Wicky BIM, Croft JT, Carter L, Bera AK, Nguyen H, Kang A, Sankaran B, Yang EC, Lee KK, Baker D. Protein Sci. 2023 Nov;32(11):e4769.

An HIV-1 broadly neutralizing antibody overcomes structural and dynamic variation through highly focused epitope targeting. Hodge EA, Chatterjee A, Chen C, Naika GJ, Laohajaratsang M, Mangala Prasad V, Lee KK. NPJ Viruses 1, 2 (2023). https://doi.org/10.1038/s44298-023-00002-4

Identification of broad, potent antibodies to functionally constrained regions of SARS-CoV-2 spike following a breakthrough infection. Guenthoer J, Lilly M, Starr TN, Dadonaite B, Lovendahl KN, Croft JT, Stoddard CI, Chohan V, Ding S, Ruiz F, Kopp MS, Finzi A, Bloom JD, Chu HY, Lee KK, Overbaugh J. Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2220948120.

hACE2-Induced Allosteric Activation in SARS-CoV versus SARS-CoV-2 Spike Assemblies Revealed by Structural Dynamics. Chen C, Zhu R, Hodge EA, Díaz-Salinas MA, Nguyen A, Munro JB, Lee KK. ACS Infect Dis. 2023 Jun 9;9(6):1180-1189.

Structural dynamics reveal subtype-specific activation and inhibition of influenza virus hemagglutinin. Garcia NK, Kephart SM, Benhaim MA, Matsui T, Mileant A, Guttman M, Lee KK. J Biol Chem. 2023 Jun;299(6):104765.

Cytoplasmic Tail Truncation Stabilizes S1-S2 Association and Enhances S Protein Incorporation into SARS-CoV-2 Pseudovirions. Zhang L, Hom N, Ojha A, Lovendahl KN, Mou H, Lee KK, Choe H. J Virol. 2023 Mar 30;97(3):e0165022.

Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses. McLeod B, Mabrouk MT, Miura K, Ravichandran R, Kephart S, Hailemariam S, Pham TP, Semesi A, Kucharska I, Kundu P, Huang WC, Johnson M, Blackstone A, Pettie D, Murphy M, Kraft JC, Leaf EM, Jiao Y, van de Vegte-Bolmer M, van Gemert GJ, Ramjith J, King CR, MacGill RS, Wu Y, Lee KK, Jore MM, King NP, Lovell JF, Julien JP. Immunity. 2022 Sep 13;55(9):1680-1692.e8.

Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery. Mangala Prasad V, Blijleven JS, Smit JM, Lee KK. Nat Commun. 2022 Aug 15;13(1):4772.

Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env.  Hodge EA, Naika GS, Kephart SM, Nguyen A, Zhu R, Benhaim MA, Guo W, Moore JP, Hu SL, Sanders RW, Lee KK. iScience. 2022 May 23;25(6):104449.

Structure-based design of stabilized recombinant influenza neuraminidase tetramers. Ellis D, Lederhofer J, Acton OJ, Tsybovsky Y, Kephart S, Yap C, Gillespie RA, Creanga A, Olshefsky A, Stephens T, Pettie D, Murphy M, Sydeman C, Ahlrichs M, Chan S, Borst AJ, Park YJ, Lee KK, Graham BS, Veesler D, King NP, Kanekiyo M. Nat Commun. 2022 Apr 5;13(1):1825.

Structure-guided changes at the V2 apex of HIV-1 clade C trimer enhance elicitation of autologous neutralizing and broad V1V2-scaffold antibodies. Sahoo A, Hodge EA, LaBranche CC, Styles TM, Shen X, Cheedarla N, Shiferaw A, Ozorowski G, Lee WH, Ward AB, Tomaras GD, Montefiori DC, Irvine DJ, Lee KK, Amara RR. Cell Rep. 2022 Mar 1;38(9):110436.

Cryo-ET of Env on intact HIV virions reveals structural variation and positioning on the Gag lattice. Mangala Prasad V, Leaman DP, Lovendahl KN, Croft JT, Benhaim MA, Hodge EA, Zwick MB, Lee KK. Cell. 2022 Feb 17;185(4):641-653.e17.

Mannose-binding lectin and complement mediate follicular localization and enhanced immunogenicity of diverse protein nanoparticle immunogens. Read BJ, Won L, Kraft JC, Sappington I, Aung A, Wu S, Bals J, Chen C, Lee KK, Lingwood D, King NP, Irvine DJ. Cell Rep. 2022 Jan 11;38(2):110217.