Structural Biology of Immune Recognition of Pathogens
Our laboratory is interested in immune recognition of viral pathogens. We are investigating the immune responses against HIV-1 and other viruses, most recently SARS-CoV-2, in order to develop improved therapeutics and/or vaccines. We use X-ray crystallography, electron microscopy, and biochemistry to study pathogen glycoproteins and host immune proteins. Using structural information and alternate antibody architectures, we are engineering antibody-based reagents with increased potency and breadth. We are also investigating the structural correlates of potent antibody-mediated neutralization of HIV-1, SARS-CoV-2, and hepatitis C virus to better understand what leads to naturally-occurring potent neutralizing antibodies. Examples of our research are described below.
- Antibody-mediated neutralization of SARS-CoV-2 and potential pan-sarbecovirus vaccine. Neutralizing antibody responses to coronaviruses focus on receptor-binding domain (RBD) of the trimeric viral spike. We characterized polyclonal antibodies from human plasmas for recognition of coronavirus spikes and RBDs and solved single-particle cryo-EM structures of antibody-spike complexes, providing rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for therapeutic use, and providing insight into immune responses against SARS-CoV-2. Using this information, we designed a vaccine approach to elicit antibodies against conserved RBD epitopes, which involves mosaic nanoparticles that presents RBDs from multiple sarbecoviruses of pandemic concern, finding reactivity against SARS-CoV-2 and its variants of concern and superior cross-reactivity against animal coronaviruses compared with homotypic RBD-nanoparticles presenting SARS-CoV-2 RBDs only. Recent results show protection from SARS-CoV-2 and SARS-CoV-1 challenge in animals vaccinated with mosaic RBD-nanoparticles, but protection only from SARS-CoV-2 challenge in homotypic RBD-nanoparticle vaccinated animals.
- Barnes, CO, West Jr., AP, Huey-Tubman, KE, Hoffmann, MAG, Sharaf, NG, Hoffman, PR, Koranda, N, Gristick, HB, Gaebler, C, Muecksch, F, Cetrulo Lorenzi, JC, Finkin, S, Hägglöf, T, Hurley, A, Millard, KG, Weisblum, Y, Schmidt, F, Hatziioannou, T, Bieniasz, PD, Caskey, M, Robbiani, DF, Nussenzweig, MC, Bjorkman, PJ (2020) Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell 182: 828-842.e16. doi:10.1016/j.cell.2020.06.025
- Barnes, CO, Jette, CA, Abernathy, MA, Dam, K-M A, Esswein, SR, Gristick, HB, Malyutin, AG, Sharaf, NG, Huey-Tubman, KE, Lee, YE, Robbiani, DF, Nussenzweig, MC, West, AP, Bjorkman, PJ (2020) Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies. Nature 588: 682-7. doi:10.1038/s41586-020-2852-1
- Cohen, AA, Gnanapragasam, PNP, Lee, YE, Hoffman, PR, Ou, S, Kakutani, LM, Keeffe, JR, Wu, H-J, Howarth, M, West, AP, Barnes, CO, Nussenzweig, MC, Bjorkman, PJ (2021) Mosaic nanoparticles elicit cross-reactive immune responses to zoonotic coronaviruses in mice. Science eabf6840 doi:10.1126/science.abf6840.
- Cohen, AA*, van Doremalen, N*, Greaney, AJ, Andersen, H, Sharma, A, Starr, TN, Keeffe, JR, Fan, C, Schulz, JE, Gnanapragasam, PNP, Kakutani, LM, West Jr., AP, Saturday, G, Lee YE, Gao, H, Jette, CA, Lewis, MG, Tan, TK, Townsend, AR, Bloom, JD, Munster, VJ, Bjorkman, PJ (2022) Mosaic RBD nanoparticles protect against diverse sarbecovirus challenges in animal models. Science *Co-first authors. doi:10.1126/science.abq0839
- HIV-1 vaccine design and structural correlates of broad and potent antibody neutralization. Designing effective strategies to combat HIV-1 requires structural knowledge of how antibodies recognize HIV envelope proteins. The availability of broadly neutralizing anti-HIV-1 antibodies (bNAbs) with unprecedented potencies offers the opportunity to determine the structural correlates of broad and potent neutralization. We solved crystal and cryo-EM structures of HIV-1 bNAbs bound to their envelope antigens, and then used a combination of structure-based rational design and bioinformatics to improve their potencies and breadth and design immunogens as vaccines. These multi-disciplinary studies revealed mechanisms by HIV-1 both successfully and unsuccessfully evades bNAbs that are relevant to current attempts to use bNAbs for prevention and/or treatment of HIV-1 infection and design of immunogens to elicit bNAbs during vaccination.
- Diskin R, Scheid JF, Marcovecchio PM, West AP, Klein F, Gao H, Gnanapragasam PNP, Abadir A, Seaman MS, Nussenzweig MC, Bjorkman PJ (2011) Increasing the potency and breadth of an HIV antibody by using structure-based rational design. Science 334: 1289-1293. doi:101126/science1213782
- *Escolano, A, *Gristick, HB, Abernathy, ME, Merkenschlager, J, Gautam, R, Oliveira, TY, Pai, J, West, AP, Barnes, CO, Cohen, AA, Wang, H, Golijanin, J, Yost, D, Keeffe, JR, Wang, Z, Zhao, P, Yao, K-H, Bauer, J, Nogueira, L, Gao, H, Voll, AV, Montefior, DC, Seaman, MS, Gazumyan, A, Silva, M, McGuire, AT, Stamatatos, L, Irvine, DJ, Wells, L, Martin, MA, *Bjorkman, PJ, *Nussenzweig, MC (2019) Immunization expands HIV-1 glycan patch-specific B-cells in mice and macaques. Nature 570: 468-73. *co-first authors/co-corresponding authors. doi:10.1038/s41586-019-1250-z
- Escolano, A*, Gristick, HB*, Gautam, R*, DeLaitsch, AT*, Abernathy, ME, Yang, Z, Wang, H, Hoffmann, MAG, Nishimura, Y, Wang, Z, Koranda, N, Kakutani, LM, Gao, H, Gnanapragasam, PNP, Raina, H, Gazumyan, A, Cipolla, M, Oliveria, TY, Ramos, V, Irvine, DJ, Silva, M, West, AP, Keeffe, JR, Barnes, CO, Seaman, MS, Nussenzweig, MC, Martin, MA, Bjorkman, PJ (2021) Sequential immunization of macaques elicits heterologous neutralizing antibodies targeting the V3-glycan patch of HIV-1 Env. Science Transl Med. doi: 10.1126/scitranslmed.abk1533. *Co-first authors.
- Gristick, HB*, Hartweger, H*, Loewe, M, van Schooten, J, Ramos, V, Oliviera, TY, Nishimura, Y, Koranda, NS, Wall, A, Yao, K-H, Poston, D, Gazumyan, A, Wiatr, M, Horning, M, Keeffe, JR, Hoffmann, MAG, Yang, Z, Abernathy, ME, Dam, KA, Gao, H, Gnanapragasam, PNP, Kakutani, LM, Pavlovitch-Bedzyk, AJ, Seaman, MS, Howarth, M, McGuire, AT, Stamatatos, L, Martin, MA, West, AP, Nussenzweig, MC, Bjorkman, PJ (2022) CD4-binding site immunogens elicit heterologous anti-HIV-1 neutralizing antibodies in transgenic and wildtype animals. Sci Immunol 8: eade6364. doi:10.1126/sciimmunol.ade6364 *Co-first authors.
- Structural studies of antibodies bound to HIV-1 Env trimers in different conformational states. HIV-1 Env undergoes conformational changes after binding to host receptor CD4 that allow coreceptor binding, resulting in fusion between host and viral membranes. Understanding Env conformational changes is critical for immunogen design. We solved cryo-EM structures of CD4-bound Envs, revealing the order of changes involved in coreceptor binding-site exposure and the structure of the rearranged V1V2 loops. The structures showed that the V1V2 region that is displaced by 40 Å from the Env trimer apex to its sides, thereby exposed the V3 region for coreceptor binding. We also characterized neutralizing antibodies raised in macaques vaccinated with one of our immunogens that recognize occluded-open Env trimers.
- Scharf, L, Wang, H, Gao, H, Chen, S, McDowall, AW, Bjorkman, PJ (2015) Broadly neutralizing antibody 8ANC195 recognizes closed and open states of HIV-1 Env. Cell 162: 1379–13. doi:101016/jcell201508035
- Wang, H, Cohen, AA, Galimidi, RP, Gristick, HB, Jensen, GJ, Bjorkman, PJ (2016). Cryo-EM structure of a CD4-bound open HIV-1 Envelope trimer reveals structural rearrangements of the gp120 V1V2 loop. Proc Natl Acad Sci USA 113: E7151-E7158. doi:10.1073/pnas.1615939113
- Wang, H, Gristick, HB, Scharf, L, West, AP, Jr, Galimidi, RP, Seaman, MS, Freund, NT, Nussenzweig, MC, Bjorkman, PJ (2017) Asymmetric recognition of HIV-1 Env trimer by V1V2 loop-targeting antibodies. eLife 6: e27389. doi:10.7554/eLife.27389
- Yang, Z, Dam K-MA, Bridges, MD, Hoffmann, MAG, DeLaitsch, AT, Gristick, HB, Escolano, A, Gautam, R, Martin, MA, Nussenzweig, MC, Hubbell, WL, Bjorkman, PJ (2022) Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer. Nat Comm 13: 732 doi:10.1038/s41467-022-28424-3
- Imaging HIV-infected tissues. Locating HIV-1 virions within infected tissue is critical for understanding how to develop a protective vaccine. We use electron tomography (3-D EM) to generate reconstructions of µm3 of well-preserved HIV-infected tissue samples at resolutions allowing identification of cells and single virions that can be classified into immature budding, immature free, and mature free states. In complementary studies, we used tissue clearing and immunofluorescence to survey large volumes (mm3-cm3) of immunostained tissues at single cell resolution from animal models of HIV-1 infection. This approach allows identification of individual HIV-infected cells within regions of tissue containing tens of thousands of cells and provides geographic information about the distribution of HIV-1 within infected tissues.
- Ladinsky, MS, Kieffer, C, Olson, G, Deruaz, M, Vrbanac, V, Tager, AM, Kwon, DS, Bjorkman, PJ (2014) Electron tomography of HIV-1 infection in gut-associated lymphoid tissue. PLoS Pathog 10 :e003899. doi: 101371/journalppat1003899
- Kieffer C, Ladinsky MS, Ninh A, Galimidi RP, Bjorkman PJ (2017) Longitudinal imaging of HIV-1 spread in humanized mice with parallel 3D immunofluorescence and electron tomography. eLife 6: e23282. doi:10.7554/eLife.2328
- Ladinsky, MS, Khamaikawin, W, Jung, Y, Lin, S, Lam, J, An, DS, Bjorkman, PJ, Kieffer, C (2019) Mechanisms of virus dissemination in bone marrow of HIV-1–infected humanized BLT mice. eLife 8: e46916. doi:10.7554/eLife.46916
- Ladinsky, MS, Gnanapragasam, PNP, Yang, Z, West Jr., AP, Kay, MS, Bjorkman PJ (2020) Electron tomography visualization of HIV-1 fusion with target cells using fusion inhibitors to trap the pre-hairpin intermediate. eLife 9 :e58411. doi:10.7554/eLife.58411
- MHC structural biology. MHC-restricted recognition of antigen by T cells is understood today as resulting from T cell receptor (TCR) binding to a peptide antigen in the groove of an MHC molecule. But the nature of MHC-restricted antigen recognition was mysterious in 1979, when as a new graduate student in Don Wiley's laboratory, I initiated a project to crystallize and solve the 3-D structure of the human class I MHC protein, HLA-A2. During this time, the altered self hypothesis for MHC-restricted antigen recognition by T cells raised the possibility that the mysterious dual recognition properties of T cells might be understood by taking the structures of a viral antigen and an MHC protein and docking them together as a complex. However, when we published the first MHC structure in 1987, the discovery of a peptide occupant in the HLA-A2 binding groove came as a surprise, rationalizing MHC-restricted antigen recognition by T cells. The finding of bound peptide(s) implied that MHC proteins always present peptides to the immune system, thus the immune system must have a way to distinguish innocuous self peptides from potentially dangerous foreign peptides, suggesting what goes wrong during an autoimmune disease: T cells mistakenly recognize a self peptide as foreign.
- Bjorkman PJ, MA Saper, B Samraoui, WS Bennett, JL Strominger and DC Wiley. (1987) Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329:506-512.
- Bjorkman PJ, MA Saper, B Samraoui, WS Bennett, JL Strominger and DC Wiley. (1987) The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329:512-518.
- Davis MM and PJ Bjorkman (1988) T cell antigen receptor genes and T cell recognition. Nature 334: 395-402.
- Fahnestock, ML, I Tamir, L Narhi and PJ Bjorkman (1992) Thermal stability comparison of purified empty and peptide-filled forms of a class I MHC molecule. Science 258: 1658-1662.
Complete list of published work in MyBibliography.
Infections with a novel coronavirus, SARS-CoV-2, resulted in a pandemic that has claimed millions of lives worldwide. In the shadow of the health crisis, scientists combined research into combatting COVID-19 with activism to improve justice for Black and other under-represented minorities.