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153. N‐Terminal Modification of Gly‐His‐Tagged Proteins with Azidogluconolactone

Author

Brune, Karl D., primary, Liekniņa, Ilva, additional, Sutov, Grigorij, additional, Morris, Alexander R., additional, Jovicevic, Dejana, additional, Kalniņš, Gints, additional, Kazāks, Andris, additional, Kluga, Rihards, additional, Kastaljana, Sabine, additional, Zajakina, Anna, additional, Jansons, Juris, additional, Skrastiņa, Dace, additional, Spunde, Karīna, additional, Cohen, Alexander A., additional, Bjorkman, Pamela J., additional, Morris, Howard R., additional, Suna, Edgars, additional, and Tārs, Kaspars, additional

Published
2021
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154. Rapid Identification of Neutralizing Antibodies against SARS-CoV-2 Variants by mRNA Display

Author

Tanaka, Shiho, primary, Anders Olson, C., additional, Barnes, Christopher O., additional, Higashide, Wendy, additional, Gonzalez, Marcos, additional, Taft, Justin, additional, Richardson, Ashley, additional, Martin-Fernandez, Marta, additional, Bogunovic, Dusan, additional, Gnanapragasam, Priyanthi N.P., additional, Bjorkman, Pamela J., additional, Spilman, Patricia, additional, Niazi, Kayvan, additional, Rabizadeh, Shahrooz, additional, and Soon-Shiong, Patrick, additional

Published
2021
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155. Live imaging of SARS-CoV-2 infection in mice reveals that neutralizing antibodies require Fc function for optimal efficacy

Author

Ullah, Irfan, primary, Prévost, Jérémie, additional, Ladinsky, Mark S., additional, Stone, Helen, additional, Lu, Maolin, additional, Anand, Sai Priya, additional, Beaudoin-Bussières, Guillaume, additional, Symmes, Kelly, additional, Benlarbi, Mehdi, additional, Ding, Shilei, additional, Gasser, Romain, additional, Fink, Corby, additional, Chen, Yaozong, additional, Tauzin, Alexandra, additional, Goyette, Guillaume, additional, Bourassa, Catherine, additional, Medjahed, Halima, additional, Mack, Matthias, additional, Chung, Kunho, additional, Wilen, Craig B., additional, Dekaban, Gregory A., additional, Dikeakos, Jimmy D., additional, Bruce, Emily A., additional, Kaufmann, Daniel E., additional, Stamatatos, Leonidas, additional, McGuire, Andrew T., additional, Richard, Jonathan, additional, Pazgier, Marzena, additional, Bjorkman, Pamela J., additional, Mothes, Walther, additional, Finzi, Andrés, additional, Kumar, Priti, additional, and Uchil, Pradeep D., additional

Published
2021
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161. HIV therapy by a combination of broadly neutralizing antibodies in humanized mice

Author

Klein, Florian, Halper-Stromberg, Ariel, Horwitz, Joshua A., Gruell, Henning, Scheid, Johannes F., Bournazos, Stylianos, Mouquet, Hugo, Spatz, Linda A., Diskin, Ron, Abadir, Alexander, Zang, Trinity, Dorner, Marcus, Billerbeck, Eva, Labitt, Rachael N., Gaebler, Christian, Marcovecchio, Paola M., Incesu, Reha-Baris, Eisenreich, Thomas R., Bieniasz, Paul D., Seaman, Michael S., Bjorkman, Pamela J., Ravetch, Jeffrey V., Ploss, Alexander, and Nussenzweig, Michel C.

Subjects
Highly active antiretroviral therapy -- Protection and preservation -- Health aspects, Monoclonal antibodies -- Usage -- Health aspects, HIV infection -- Protection and preservation -- Health aspects -- Development and progression -- Drug therapy -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection (1,2). Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time (3,4). However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design (5-9). Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy (10-12), the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1-infected individuals., Treatment of HIV-1 infection was ineffective until antiretroviral drugs were applied in combination, permitting sustained suppression of viraemia (13,14). Despite this resounding success, the burden of daily medication, side effects [...]

Published
2012

162. Severe Acute Respiratory Syndrome Coronavirus 2 Viremia Is Associated With Coronavirus Disease 2019 Severity and Predicts Clinical Outcomes

Author

Jacobs, Jana L, primary, Bain, William, additional, Naqvi, Asma, additional, Staines, Brittany, additional, Castanha, Priscila M S, additional, Yang, Haopu, additional, Boltz, Valerie F, additional, Barratt-Boyes, Simon, additional, Marques, Ernesto T A, additional, Mitchell, Stephanie L, additional, Methé, Barbara, additional, Olonisakin, Tolani F, additional, Haidar, Ghady, additional, Burke, Thomas W, additional, Petzold, Elizabeth, additional, Denny, Thomas, additional, Woods, Chris W, additional, McVerry, Bryan J, additional, Lee, Janet S, additional, Watkins, Simon C, additional, St Croix, Claudette M, additional, Morris, Alison, additional, Kearney, Mary F, additional, Ladinsky, Mark S, additional, Bjorkman, Pamela J, additional, Kitsios, Georgios D, additional, and Mellors, John W, additional

Published
2021
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163. Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations

Author

Muecksch, Frauke, primary, Weisblum, Yiska, additional, Barnes, Christopher O., additional, Schmidt, Fabian, additional, Schaefer-Babajew, Dennis, additional, Wang, Zijun, additional, C. Lorenzi, Julio C., additional, Flyak, Andrew I., additional, DeLaitsch, Andrew T., additional, Huey-Tubman, Kathryn E., additional, Hou, Shurong, additional, Schiffer, Celia A., additional, Gaebler, Christian, additional, Da Silva, Justin, additional, Poston, Daniel, additional, Finkin, Shlomo, additional, Cho, Alice, additional, Cipolla, Melissa, additional, Oliveira, Thiago Y., additional, Millard, Katrina G., additional, Ramos, Victor, additional, Gazumyan, Anna, additional, Rutkowska, Magdalena, additional, Caskey, Marina, additional, Nussenzweig, Michel C., additional, Bjorkman, Pamela J., additional, Hatziioannou, Theodora, additional, and Bieniasz, Paul D., additional

Published
2021
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168. Intestinal Host Response to SARS-CoV-2 Infection and COVID-19 Outcomes in Patients With Gastrointestinal Symptoms

Author

Livanos, Alexandra E., primary, Jha, Divya, additional, Cossarini, Francesca, additional, Gonzalez-Reiche, Ana S., additional, Tokuyama, Minami, additional, Aydillo, Teresa, additional, Parigi, Tommaso L., additional, Ladinsky, Mark S., additional, Ramos, Irene, additional, Dunleavy, Katie, additional, Lee, Brian, additional, Dixon, Rebekah E., additional, Chen, Steven T., additional, Martinez-Delgado, Gustavo, additional, Nagula, Satish, additional, Bruce, Emily A., additional, Ko, Huaibin M., additional, Glicksberg, Benjamin S., additional, Nadkarni, Girish, additional, Pujadas, Elisabet, additional, Reidy, Jason, additional, Naymagon, Steven, additional, Grinspan, Ari, additional, Ahmad, Jawad, additional, Tankelevich, Michael, additional, Bram, Yaron, additional, Gordon, Ronald, additional, Sharma, Keshav, additional, Houldsworth, Jane, additional, Britton, Graham J., additional, Chen-Liaw, Alice, additional, Spindler, Matthew P., additional, Plitt, Tamar, additional, Wang, Pei, additional, Cerutti, Andrea, additional, Faith, Jeremiah J., additional, Colombel, Jean-Frederic, additional, Kenigsberg, Ephraim, additional, Argmann, Carmen, additional, Merad, Miriam, additional, Gnjatic, Sacha, additional, Harpaz, Noam, additional, Danese, Silvio, additional, Cordon-Cardo, Carlos, additional, Rahman, Adeeb, additional, Schwartz, Robert E., additional, Kumta, Nikhil A., additional, Aghemo, Alessio, additional, Bjorkman, Pamela J., additional, Petralia, Francesca, additional, van Bakel, Harm, additional, Garcia-Sastre, Adolfo, additional, and Mehandru, Saurabh, additional

Published
2021
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169. B cell genomics behind cross-neutralization of SARS-CoV-2 variants and SARS-CoV

Author

Scheid, Johannes F., primary, Barnes, Christopher O., additional, Eraslan, Basak, additional, Hudak, Andrew, additional, Keeffe, Jennifer R., additional, Cosimi, Lisa A., additional, Brown, Eric M., additional, Muecksch, Frauke, additional, Weisblum, Yiska, additional, Zhang, Shuting, additional, Delorey, Toni, additional, Woolley, Ann E., additional, Ghantous, Fadi, additional, Park, Sung-Moo, additional, Phillips, Devan, additional, Tusi, Betsabeh, additional, Huey-Tubman, Kathryn E., additional, Cohen, Alexander A., additional, Gnanapragasam, Priyanthi N.P., additional, Rzasa, Kara, additional, Hatziioanno, Theodora, additional, Durney, Michael A., additional, Gu, Xiebin, additional, Tada, Takuya, additional, Landau, Nathaniel R., additional, West, Anthony P., additional, Rozenblatt-Rosen, Orit, additional, Seaman, Michael S., additional, Baden, Lindsey R., additional, Graham, Daniel B., additional, Deguine, Jacques, additional, Bieniasz, Paul D., additional, Regev, Aviv, additional, Hung, Deborah, additional, Bjorkman, Pamela J., additional, and Xavier, Ramnik J., additional

Published
2021
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170. N‐Terminal Modification of Gly‐His‐Tagged Proteins with Azidogluconolactone

Author

Brune, Karl D., Liekniņa, Ilva, Sutov, Grigorij, Morris, Alexander R., Jovicevic, Dejana, Kalniņš, Gints, Kazāks, Andris, Kluga, Rihards, Kastaljana, Sabine, Zajakina, Anna, Jansons, Juris, Skrastiņa, Dace, Spunde, Karīna, Cohen, Alexander A., Bjorkman, Pamela J., Morris, Howard R., Suna, Edgars, Tārs, Kaspars, Brune, Karl D., Liekniņa, Ilva, Sutov, Grigorij, Morris, Alexander R., Jovicevic, Dejana, Kalniņš, Gints, Kazāks, Andris, Kluga, Rihards, Kastaljana, Sabine, Zajakina, Anna, Jansons, Juris, Skrastiņa, Dace, Spunde, Karīna, Cohen, Alexander A., Bjorkman, Pamela J., Morris, Howard R., Suna, Edgars, and Tārs, Kaspars

Abstract

Site-selective α-amino acylation of proteins with N-terminal Gly-HisTags using 6-azido-6-deoxy-glucono-1,5-lactone (6AGDL) is reported. To demonstrate the usefulness of this reaction, we multimerise the SARS-CoV-2 receptor-binding domain (RBD) protein antigen onto virus-like particles (VLPs) via strain-promoted alkyne-azide cycloaddition (SPAAC). The resulting COVID-19 vaccine candidate induces single-shot seroconversion, and virus-neutralizing antibodies in mice.

Published
2021

171. Rapid Identification of Neutralizing Antibodies against SARS-CoV-2 Variants by mRNA Display

Author

Tanaka, Shiho, Olson, C. Anders, Barnes, Christopher O., Higashide, Wendy, Gonzales, Marcos, Taft, Justin, Richardson, Ashley, Martin-Fernandez, Marta, Bogunovic, Dusan, Gnanapragasam, Priyanthi N. P., Bjorkman, Pamela J., Spilman, Patricia, Niazi, Kayvan, Rabizadeh, Shahrooz, Soon-Shiong, Patrick, Tanaka, Shiho, Olson, C. Anders, Barnes, Christopher O., Higashide, Wendy, Gonzales, Marcos, Taft, Justin, Richardson, Ashley, Martin-Fernandez, Marta, Bogunovic, Dusan, Gnanapragasam, Priyanthi N. P., Bjorkman, Pamela J., Spilman, Patricia, Niazi, Kayvan, Rabizadeh, Shahrooz, and Soon-Shiong, Patrick

Abstract

The increasing prevalence of SARS-CoV-2 variants with the ability to escape existing humoral protection conferred by previous infection and/or immunization necessitates the discovery of broadly-reactive neutralizing antibodies (nAbs). Utilizing mRNA display, we identified a set of antibodies against SARS-CoV-2 spike (S) proteins and characterized the structures of nAbs that recognized epitopes in the S1 subunit of the S glycoprotein. These structural studies revealed distinct binding modes for several antibodies, including targeting of rare cryptic epitopes in the receptor-binding domain (RBD) of S that interacts with angiotensin-converting enzyme 2 (ACE2) to initiate infection, as well as the S1 subdomain 1. A potent ACE2-blocking nAb was further engineered to sustain binding to S RBD with the E484K and L452R substitutions found in multiple SARS-CoV-2 variants. We demonstrate that mRNA display is a promising approach for the rapid identification of nAbs that can be used in combination to combat emerging SARS-CoV-2 variants.

Published
2021

172. Neutralizing antibodies against coronaviruses

Author

Bjorkman, Pamela J. and Bjorkman, Pamela J.

Abstract

The SARS-CoV-2 virus has caused a world-wide pandemic resulting in a massive loss of lives and detrimental effects on the economies of most countries. We are using single-particle cryo-electron microscopy (cryo-EM) to solve structures of infection- and vaccination-induced antibodies complexed with the spike trimer of SARS-CoV-2 in order to elucidate the structural correlates of antibody-based immune protection. Structural comparisons allowed us to classify antibodies against the receptor-binding domain (RBD) of spike trimer into categories. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, and suggesting combinations for clin. use, and provide insight into immune responses against SARS-CoV-2. Our structural studies have also guided the development of a potential pan-betacoronavirus vaccine. The vaccine approach involves co-display of diverse sets of RBDs from SARS-like beta coronaviruses (sarbecoviruses) on nanoparticles (mosaic-RBD-nanoparticles) that results in increased breadth of neutralizing responses in mice compared with nanoparticles presenting only SARS-CoV-2 RBDs. This modular vaccine platform could provide protection from SARS-CoV-2 as well as potential future emergent coronaviruses that could cause pandemics.

Published
2021

173. Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies

Author

Muecksch, Frauke, Weisblum, Yiska, Barnes, Christopher O., Schmidt, Fabian, Schaefer-Babajew, Dennis, Lorenzi, Julio C. C., Flyak, Andrew I., DeLaitsch, Andrew T., Huey-Tubman, Kathryn E., Hou, Shurong, Schiffer, Celia A., Gaebler, Christian, Wang, Zijun, Da Silva, Justin, Poston, Daniel, Finkin, Shlomo, Cho, Alice, Cipolla, Melissa, Oliveira, Thiago Y., Millard, Katrina G., Ramos, Victor, Gazumyan, Anna, Rutkowska, Magdalena, Caskey, Marina, Nussenzweig, Michel C., Bjorkman, Pamela J., Hatziioannou, Theodora, Bieniasz, Paul D., Muecksch, Frauke, Weisblum, Yiska, Barnes, Christopher O., Schmidt, Fabian, Schaefer-Babajew, Dennis, Lorenzi, Julio C. C., Flyak, Andrew I., DeLaitsch, Andrew T., Huey-Tubman, Kathryn E., Hou, Shurong, Schiffer, Celia A., Gaebler, Christian, Wang, Zijun, Da Silva, Justin, Poston, Daniel, Finkin, Shlomo, Cho, Alice, Cipolla, Melissa, Oliveira, Thiago Y., Millard, Katrina G., Ramos, Victor, Gazumyan, Anna, Rutkowska, Magdalena, Caskey, Marina, Nussenzweig, Michel C., Bjorkman, Pamela J., Hatziioannou, Theodora, and Bieniasz, Paul D.

Abstract

Antibodies elicited in response to infection undergo somatic mutation in germinal centers that can result in higher affinity for the cognate antigen. To determine the effects of somatic mutation on the properties of SARS-CoV-2 spike receptor-binding domain (RBD)-specific antibodies, we analyzed six independent antibody lineages. As well as increased neutralization potency, antibody evolution changed pathways for acquisition of resistance and, in some cases, restricted the range of neutralization escape options. For some antibodies, maturation apparently imposed a requirement for multiple spike mutations to enable escape. For certain antibody lineages, maturation enabled neutralization of circulating SARS-CoV-2 variants of concern and heterologous sarbecoviruses. Antibody-antigen structures revealed that these properties resulted from substitutions that allowed additional variability at the interface with the RBD. These findings suggest that increasing antibody diversity through prolonged or repeated antigen exposure may improve protection against diversifying SARS-CoV-2 populations, and perhaps against other pandemic threat coronaviruses.

Published
2021

174. Detection and characterization of the SARS-CoV-2 lineage B.1.526 in New York.

Author

West, Anthony P, West, Anthony P, Wertheim, Joel O, Wang, Jade C, Vasylyeva, Tetyana I, Havens, Jennifer L, Chowdhury, Moinuddin A, Gonzalez, Edimarlyn, Fang, Courtney E, Di Lonardo, Steve S, Hughes, Scott, Rakeman, Jennifer L, Lee, Henry H, Barnes, Christopher O, Gnanapragasam, Priyanthi NP, Yang, Zhi, Gaebler, Christian, Caskey, Marina, Nussenzweig, Michel C, Keeffe, Jennifer R, Bjorkman, Pamela J, West, Anthony P, West, Anthony P, Wertheim, Joel O, Wang, Jade C, Vasylyeva, Tetyana I, Havens, Jennifer L, Chowdhury, Moinuddin A, Gonzalez, Edimarlyn, Fang, Courtney E, Di Lonardo, Steve S, Hughes, Scott, Rakeman, Jennifer L, Lee, Henry H, Barnes, Christopher O, Gnanapragasam, Priyanthi NP, Yang, Zhi, Gaebler, Christian, Caskey, Marina, Nussenzweig, Michel C, Keeffe, Jennifer R, and Bjorkman, Pamela J

Abstract

Wide-scale SARS-CoV-2 genome sequencing is critical to tracking viral evolution during the ongoing pandemic. Variants first detected in the United Kingdom, South Africa, and Brazil have spread to multiple countries. We developed the software tool, Variant Database (VDB), for quickly examining the changing landscape of spike mutations. Using VDB, we detected an emerging lineage of SARS-CoV-2 in the New York region that shares mutations with previously reported variants. The most common sets of spike mutations in this lineage (now designated as B.1.526) are L5F, T95I, D253G, E484K or S477N, D614G, and A701V. This lineage was first sequenced in late November 2020 when it represented <1% of sequenced coronavirus genomes that were collected in New York City (NYC). By February 2021, genomes from this lineage accounted for ~ 32% of 3288 sequenced genomes from NYC specimens. Phylodynamic inference confirmed the rapid growth of the B.1.526 lineage in NYC, notably the sub-clade defined by the spike mutation E484K, which has outpaced the growth of other variants in NYC. Pseudovirus neutralization experiments demonstrated that B.1.526 spike mutations adversely affect the neutralization titer of convalescent and vaccinee plasma, indicating the public health importance of this lineage.

Published
2021

176. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1

Author

Li, Li, Fang, Celia J., Ryan, James C., Niemi, Erene C., Lebron, Jose A., Bjorkman, Pamela J., Arase, Hisashi, Torti, Frank M., Torti, Suzy V., Nakamura, Mary C., and Seaman, William E.

Subjects
Protein binding -- Research, Ferritin -- Chemical properties, Transferrin -- Chemical properties, Science and technology
Abstract

Ferritin is a spherical molecule composed of 24 subunits of two types, ferritin H chain (FHC) and ferritin L chain (FLC). Ferritin stores iron within cells, but it also circulates and binds specifically and saturably to a variety of cell types. For most cell types, this binding can be mediated by ferritin composed only of FHC (HFt) but not by ferritin composed only of FLC (LFt), indicating that binding of ferritin to cells is mediated by FHC but not FLC. By using expression cloning, we identified human transferrin receptor-1 (TfR1) as an important receptor for HFt with little or no binding to LFt. In vitro, HFt can be precipitated by soluble TfR1, showing that this interaction is not dependent on other proteins. Binding of HFt to TfR1 is partially inhibited by diferric transferrin, but it is hindered little, if at all, by HFE. After binding of HFt to TfR1 on the cell surface, HFt enters both endosomes and lysosomes. TfRI accounts for most, if not all, of the binding of HFt to mitogen-activated T and B cells, circulating reticulocytes, and all cell lines that we have studied. The demonstration that TfR1 can bind HFt as well as Tf raises the possibility that this dual receptor function may coordinate the processing and use of iron by these iron-binding molecules. ferritin | HFE | iron | receptors | endocytosis doi/10.1073/pnas.0913192107

Published
2010

179. Intermediate conformations of CD4-bound HIV-1 Env heterotrimers

Author

Dam, Kim-Marie A., Fan, Chengcheng, Yang, Zhi, and Bjorkman, Pamela J.

Abstract

HIV-1 envelope (Env) exhibits distinct conformational changes in response to host receptor (CD4) engagement. Env, a trimer of gp120 and gp41 heterodimers, has been structurally characterized in a closed, prefusion conformation with closely associated gp120s and coreceptor binding sites on gp120 V3 hidden by V1V2 loops1–4and in fully saturated CD4-bound open Env conformations with changes including outwardly rotated gp120s and displaced V1V2 loops3–9. To investigate changes resulting from substoichiometric CD4 binding, we solved single-particle cryo-electron microscopy (cryo-EM) structures of soluble, native-like heterotrimeric Envs bound to one or two CD4 molecules. Most of the Env trimers bound to one CD4 adopted the closed, prefusion Env state, with a minority exhibiting a heterogeneous partially open Env conformation. When bound to two CD4s, the CD4-bound gp120s exhibited an open Env conformation including a four-stranded gp120 bridging sheet and displaced gp120 V1V2 loops that expose the coreceptor sites on V3. The third gp120 adopted an intermediate, occluded-open state10that showed gp120 outward rotation but maintained the prefusion three-stranded gp120 bridging sheet with only partial V1V2 displacement and V3 exposure. We conclude that most of the engagements with one CD4 molecule were insufficient to stimulate CD4-induced conformational changes, whereas binding two CD4 molecules led to Env opening in CD4-bound protomers only. The substoichiometric CD4-bound soluble Env heterotrimer structures resembled counterparts derived from a cryo-electron tomography study of complexes between virion-bound Envs and membrane-anchored CD4 (ref. 11), validating their physiological relevance. Together, these results illuminate intermediate conformations of HIV-1 Env and illustrate its structural plasticity.

Published
2023
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180. Investigate the origins of COVID-19

Author

Bloom, Jesse D., primary, Chan, Yujia Alina, additional, Baric, Ralph S., additional, Bjorkman, Pamela J., additional, Cobey, Sarah, additional, Deverman, Benjamin E., additional, Fisman, David N., additional, Gupta, Ravindra, additional, Iwasaki, Akiko, additional, Lipsitch, Marc, additional, Medzhitov, Ruslan, additional, Neher, Richard A., additional, Nielsen, Rasmus, additional, Patterson, Nick, additional, Stearns, Tim, additional, van Nimwegen, Erik, additional, Worobey, Michael, additional, and Relman, David A., additional

Published
2021
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182. Comparing methods for immobilizing HIV-1 SOSIPs in ELISAs that evaluate antibody binding.

Author

Dam, Kim-Marie A., Mutia, Patricia S., and Bjorkman, Pamela J.

Subjects
HIV, STREPTAVIDIN, THERAPEUTIC immobilization, ENZYME-linked immunosorbent assay, IMMUNOGLOBULINS, BINDING sites
Abstract

Enzyme-linked immunosorbent assays (ELISAs) are used to evaluate binding of broadly neutralizing antibodies (bNAbs) and polyclonal sera to native-like HIV-1 Env SOSIPs. Methods for immobilizing SOSIPs on plates differ, which can lead to variable or, in some cases, misleading results. Three methods used to immobilize SOSIPs were compared to determine how antigen immobilization methods affect Env conformation and ELISA results. HIV-1 SOSIPs were directly coated on polystyrene plates, captured by a monoclonal antibody against a C-terminal affinity tag, or randomly biotinylated and coated on a streptavidin plate. Binding of bNAbs with known epitopes were compared for each immobilization method. Binding of bNAbs targeting the V1V2, V3, CD4 binding site, and gp120/gp41 interface was comparable for all antigen immobilization methods. However, directly coated HIV-1 SOSIP ELISAs showed detectable binding of 17b, a CD4-induced antibody that binds a V3 epitope that is concealed on closed prefusion Env trimers in the absence of added CD4, whereas antibody-immobilized and randomly biotinylated Env-coated ELISAs did not show detectable binding of 17b in the absence of CD4. We conclude direct coating of HIV-1 SOSIPs on ELISA plates can result in exposure of CD4-induced antibody epitopes, suggesting disruption of Env structure and exposure of epitopes that are hidden in the closed, prefusion trimer. [ABSTRACT FROM AUTHOR]

Published
2022
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183. Computational identification of HCV neutralizing antibodies with a common HCDR3 disulfide bond motif in the antibody repertoires of infected individuals.

Author

Bozhanova, Nina G., Flyak, Andrew I., Brown, Benjamin P., Ruiz, Stormy E., Salas, Jordan, Rho, Semi, Bombardi, Robin G., Myers, Luke, Soto, Cinque, Bailey, Justin R., Crowe Jr., James E., Bjorkman, Pamela J., and Meiler, Jens

Abstract

Despite recent success in hepatitis C virus (HCV) treatment using antivirals, an HCV vaccine is still needed to prevent reinfections in treated patients, to avert the emergence of drug-resistant strains, and to provide protection for people with no access to the antiviral therapeutics. The early production of broadly neutralizing antibodies (bNAbs) associates with HCV clearance. Several potent bNAbs bind a conserved HCV glycoprotein E2 epitope using an unusual heavy chain complementarity determining region 3 (HCDR3) containing an intra-loop disulfide bond. Isolation of additional structurally-homologous bNAbs would facilitate the recognition of key determinants of such bNAbs and guide rational vaccine design. Here we report the identification of new antibodies containing an HCDR3 disulfide bond motif using computational screening with the Rosetta software. Using the newly-discovered and already-known members of this antibody family, we review the required HCDR3 amino acid composition and propose determinants for the bent versus straight HCDR3 loop conformation observed in these antibodies. Identifying determinants of broadly neutralizing antibodies against hepatitis C virus (HCV) may guide HCV vaccine design. Here, the authors discover new anti-HCV antibodies using computational screening and analyze the amino acid composition and sequence-structure relationships in this antibody family. [ABSTRACT FROM AUTHOR]

Published
2022
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184. Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

Author

Agudelo, Marianna, primary, Palus, Martin, additional, Keeffe, Jennifer R., additional, Bianchini, Filippo, additional, Svoboda, Pavel, additional, Salát, Jiří, additional, Peace, Avery, additional, Gazumyan, Anna, additional, Cipolla, Melissa, additional, Kapoor, Tania, additional, Guidetti, Francesca, additional, Yao, Kai-Hui, additional, Elsterová, Jana, additional, Teislerová, Dana, additional, Chrdle, Aleš, additional, Hönig, Václav, additional, Oliveira, Thiago, additional, West, Anthony P., additional, Lee, Yu E., additional, Rice, Charles M., additional, MacDonald, Margaret R., additional, Bjorkman, Pamela J., additional, Růžek, Daniel, additional, Robbiani, Davide F., additional, and Nussenzweig, Michel C., additional

Published
2021
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186. Bispecific IgG neutralizes SARS-CoV-2 variants and prevents escape in mice

Author

De Gasparo, Raoul, primary, Pedotti, Mattia, additional, Simonelli, Luca, additional, Nickl, Petr, additional, Muecksch, Frauke, additional, Cassaniti, Irene, additional, Percivalle, Elena, additional, Lorenzi, Julio C. C., additional, Mazzola, Federica, additional, Magrì, Davide, additional, Michalcikova, Tereza, additional, Haviernik, Jan, additional, Honig, Vaclav, additional, Mrazkova, Blanka, additional, Polakova, Natalie, additional, Fortova, Andrea, additional, Tureckova, Jolana, additional, Iatsiuk, Veronika, additional, Di Girolamo, Salvatore, additional, Palus, Martin, additional, Zudova, Dagmar, additional, Bednar, Petr, additional, Bukova, Ivana, additional, Bianchini, Filippo, additional, Mehn, Dora, additional, Nencka, Radim, additional, Strakova, Petra, additional, Pavlis, Oto, additional, Rozman, Jan, additional, Gioria, Sabrina, additional, Sammartino, Josè Camilla, additional, Giardina, Federica, additional, Gaiarsa, Stefano, additional, Pan-Hammarström, Qiang, additional, Barnes, Christopher O., additional, Bjorkman, Pamela J., additional, Calzolai, Luigi, additional, Piralla, Antonio, additional, Baldanti, Fausto, additional, Nussenzweig, Michel C., additional, Bieniasz, Paul D., additional, Hatziioannou, Theodora, additional, Prochazka, Jan, additional, Sedlacek, Radislav, additional, Robbiani, Davide F., additional, Ruzek, Daniel, additional, and Varani, Luca, additional

Published
2021
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187. Live Imaging of SARS-CoV-2 Infection in Mice Reveals Neutralizing Antibodies Require Fc Function for Optimal Efficacy

Author

Ullah, Irfan, primary, Prévost, Jérémie, additional, Ladinsky, Mark S, additional, Stone, Helen, additional, Lu, Maolin, additional, Anand, Sai Priya, additional, Beaudoin-Bussières, Guillaume, additional, Symmes, Kelly, additional, Benlarbi, Mehdi, additional, Ding, Shilei, additional, Gasser, Romain, additional, Fink, Corby, additional, Chen, Yaozong, additional, Tauzin, Alexandra, additional, Goyette, Guillaume, additional, Bourassa, Catherine, additional, Medjahed, Halima, additional, Mack, Matthias, additional, Chung, Kunho, additional, Wilen, Craig B, additional, Dekaban, Gregory A., additional, Dikeakos, Jimmy D., additional, Bruce, Emily A., additional, Kaufmann, Daniel E, additional, Stamatatos, Leonidas, additional, McGuire, Andrew T., additional, Richard, Jonathan, additional, Pazgier, Marzena, additional, Bjorkman, Pamela J., additional, Mothes, Walther, additional, Finzi, Andrés, additional, Kumar, Priti, additional, and Uchil, Pradeep D., additional

Published
2021
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188. Mutational escape from the polyclonal antibody response to SARS-CoV-2 infection is largely shaped by a single class of antibodies

Author

Greaney, Allison J., primary, Starr, Tyler N., additional, Barnes, Christopher O., additional, Weisblum, Yiska, additional, Schmidt, Fabian, additional, Caskey, Marina, additional, Gaebler, Christian, additional, Cho, Alice, additional, Agudelo, Marianna, additional, Finkin, Shlomo, additional, Wang, Zijun, additional, Poston, Daniel, additional, Muecksch, Frauke, additional, Hatziioannou, Theodora, additional, Bieniasz, Paul D., additional, Robbiani, Davide F., additional, Nussenzweig, Michel C., additional, Bjorkman, Pamela J., additional, and Bloom, Jesse D., additional

Published
2021
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189. Antibody elicited by HIV-1 immunogen vaccination in macaques displaces Env fusion peptide and destroys a neutralizing epitope

Author

Abernathy, Morgan E., primary, Gristick, Harry B., additional, Vielmetter, Jost, additional, Keeffe, Jennifer R., additional, Gnanapragasam, Priyanthi NP, additional, Lee, Yu E., additional, Escolano, Amelia, additional, Gautam, Rajeev, additional, Seaman, Michael S., additional, Martin, Malcolm A., additional, Nussenzweig, Michel C., additional, and Bjorkman, Pamela J., additional

Published
2021
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190. Development of potency, breadth and resilience to viral escape mutations in SARS-CoV-2 neutralizing antibodies

Author

Muecksch, Frauke, primary, Weisblum, Yiska, additional, Barnes, Christopher O., additional, Schmidt, Fabian, additional, Schaefer-Babajew, Dennis, additional, Lorenzi, Julio C C, additional, Flyak, Andrew I, additional, DeLaitsch, Andrew T, additional, Huey-Tubman, Kathryn E, additional, Hou, Shurong, additional, Schiffer, Celia A., additional, Gaebler, Christian, additional, Wang, Zijun, additional, Da Silva, Justin, additional, Poston, Daniel, additional, Finkin, Shlomo, additional, Cho, Alice, additional, Cipolla, Melissa, additional, Oliveira, Thiago Y., additional, Millard, Katrina G., additional, Ramos, Victor, additional, Gazumyan, Anna, additional, Rutkowska, Magdalena, additional, Caskey, Marina, additional, Nussenzweig, Michel C., additional, Bjorkman, Pamela J., additional, Hatziioannou, Theodora, additional, and Bieniasz, Paul D., additional

Published
2021
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192. Lower Respiratory Tract Myeloid Cells Harbor SARS-Cov-2 and Display an Inflammatory Phenotype

Author

Bain, William G., primary, Peñaloza, Hernán F., additional, Ladinsky, Mark S., additional, van der Geest, Rick, additional, Sullivan, Mara, additional, Ross, Mark, additional, Kitsios, Georgios D., additional, Methé, Barbara A., additional, McVerry, Bryan J., additional, Morris, Alison, additional, Watson, Alan M., additional, Watkins, Simon C., additional, St Croix, Claudette M., additional, Stolz, Donna B., additional, Bjorkman, Pamela J., additional, and Lee, Janet S., additional

Published
2021
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193. FcRn-mediated antibody transport across epithelial cells revealed by electron tomography

Author

He, Wanzhong, Ladinsky, Mark S., Huey-Tubman, Kathryn E., Jensen, Grant J., McIntosh, J. Richard, and Bjorkman, Pamela J.

Subjects
Immunoadsorption -- Research, Receptor antibodies -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation, Research
Abstract

The neonatal Fc receptor (FcRn) transports maternal IgG across epithelial barriers (1,2), thereby providing the fetus or newborn with humoral immunity before its immune system is fully functional. In newborn [...]

Published
2008

194. A combination of two human monoclonal antibodies limits fetal damage by Zika virus in macaques.

Author

Van Rompay, Koen KA, Van Rompay, Koen KA, Coffey, Lark L, Kapoor, Tania, Gazumyan, Anna, Keesler, Rebekah I, Jurado, Andrea, Peace, Avery, Agudelo, Marianna, Watanabe, Jennifer, Usachenko, Jodie, Singapuri, Anil, Immareddy, Ramya, Ardeshir, Amir, Stuart, Jackson B, Bournazos, Stylianos, Ravetch, Jeffrey V, Balderes, Paul J, Lorenz, Ivo C, Esswein, Shannon R, Keeffe, Jennifer R, Bjorkman, Pamela J, Wang, Qiao, Rice, Charles M, MacDonald, Margaret R, Nussenzweig, Michel C, Robbiani, Davide F, Van Rompay, Koen KA, Van Rompay, Koen KA, Coffey, Lark L, Kapoor, Tania, Gazumyan, Anna, Keesler, Rebekah I, Jurado, Andrea, Peace, Avery, Agudelo, Marianna, Watanabe, Jennifer, Usachenko, Jodie, Singapuri, Anil, Immareddy, Ramya, Ardeshir, Amir, Stuart, Jackson B, Bournazos, Stylianos, Ravetch, Jeffrey V, Balderes, Paul J, Lorenz, Ivo C, Esswein, Shannon R, Keeffe, Jennifer R, Bjorkman, Pamela J, Wang, Qiao, Rice, Charles M, MacDonald, Margaret R, Nussenzweig, Michel C, and Robbiani, Davide F

Abstract

Human infection by Zika virus (ZIKV) during pregnancy can lead to vertical transmission and fetal aberrations, including microcephaly. Prophylactic administration of antibodies can diminish or prevent ZIKV infection in animal models, but whether passive immunization can protect nonhuman primates and their fetuses during pregnancy has not been determined. Z004 and Z021 are neutralizing monoclonal antibodies to domain III of the envelope (EDIII) of ZIKV. Together the two antibodies protect nonpregnant macaques against infection even after Fc modifications to prevent antibody-dependent enhancement (ADE) in vitro and extend their half-lives. Here we report on prophylactic coadministration of the Fc-modified antibodies to pregnant rhesus macaques challenged three times with ZIKV during first and second trimester. The two antibodies did not entirely eliminate maternal viremia but limited vertical transmission, protecting the fetus from neurologic damage. Thus, maternal passive immunization with two antibodies to EDIII can shield primate fetuses from the harmful effects of ZIKV.

Published
2020

195. An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein.

Author

Flyak, Andrew I, Flyak, Andrew I, Ruiz, Stormy E, Salas, Jordan, Rho, Semi, Bailey, Justin R, Bjorkman, Pamela J, Flyak, Andrew I, Flyak, Andrew I, Ruiz, Stormy E, Salas, Jordan, Rho, Semi, Bailey, Justin R, and Bjorkman, Pamela J

Abstract

A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs.

Published
2020

196. Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Author

Schommers, Philipp, Gruell, Henning, Abernathy, Morgan E., Tran, My-Kim, Dingens, Adam S., Gristick, Harry B., Barnes, Christopher O., Schoofs, Till, Schlotz, Maike, Vanshylla, Kanika, Kreer, Christoph, Weiland, Daniela, Holtick, Udo, Scheid, Christof, Valter, Markus M., van Gils, Marit J., Sanders, Rogier W., Vehreschild, Joerg J., Cornely, Oliver A., Lehmann, Clara, Faetkenheuer, Gerd, Seaman, Michael S., Bloom, Jesse D., Bjorkman, Pamela J., Klein, Florian, Schommers, Philipp, Gruell, Henning, Abernathy, Morgan E., Tran, My-Kim, Dingens, Adam S., Gristick, Harry B., Barnes, Christopher O., Schoofs, Till, Schlotz, Maike, Vanshylla, Kanika, Kreer, Christoph, Weiland, Daniela, Holtick, Udo, Scheid, Christof, Valter, Markus M., van Gils, Marit J., Sanders, Rogier W., Vehreschild, Joerg J., Cornely, Oliver A., Lehmann, Clara, Faetkenheuer, Gerd, Seaman, Michael S., Bloom, Jesse D., Bjorkman, Pamela J., and Klein, Florian

Abstract

Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new V(H)1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 mu g/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-angstrom cryo-EM structure of a 1-18-BG505(SOSIP.664) Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.

Published
2020

197. Structural classification of neutralizing antibodies against the SARS-CoV-2 spike receptor-binding domain suggests vaccine and therapeutic strategies

Author

Barnes, Christopher O., Jette, Claudia A., Abernathy, Morgan E., Dam, Kim-Marie A., Esswein, Shannon R., Gristick, Harry B., Malyutin, Andrey G., Sharaf, Naima G., Huey-Tubman, Kathryn E., Lee, Yu E., Robbiani, Davide F., Nussenzweig, Michel C., West, Anthony P., Jr., Bjorkman, Pamela J., Barnes, Christopher O., Jette, Claudia A., Abernathy, Morgan E., Dam, Kim-Marie A., Esswein, Shannon R., Gristick, Harry B., Malyutin, Andrey G., Sharaf, Naima G., Huey-Tubman, Kathryn E., Lee, Yu E., Robbiani, Davide F., Nussenzweig, Michel C., West, Anthony P., Jr., and Bjorkman, Pamela J.

Abstract

The COVID-19 pandemic presents an urgent health crisis. Human neutralizing antibodies (hNAbs) that target the host ACE2 receptor-binding domain (RBD) of the SARS-CoV-2 spike show therapeutic promise and are being evaluated clincally. To determine structural correlates of SARS-CoV-2 neutralization, we solved 8 new structures of distinct COVID-19 hNAbs in complex with SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed classification into categories: (1) VH3-53 hNAbs with short CDRH3s that block ACE2 and bind only to “up” RBDs, (2) ACE2-blocking hNAbs that bind both “up” and “down” RBDs and can contact adjacent RBDs, (3) hNAbs that bind outside the ACE2 site and recognize “up” and “down” RBDs, and (4) Previously-described antibodies that do not block ACE2 and bind only “up” RBDs. Class 2 comprised four hNAbs whose epitopes bridged RBDs, including a VH3-53 hNAb that used a long CDRH3 with a hydrophobic tip to bridge between adjacent “down” RBDs, thereby locking spike into a closed conformation. Epitope/paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally-occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects, suggesting combinations for clinical use, and providing insight into immune responses against SARS-CoV-2.

Published
2020

198. Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody

Author

Schommers, Philipp Frederik, Gruell, Henning, Abernathy, Morgan E., Tran, My-Kim, Dingens, Adam S., Gristick, Harry B., Barnes, Christopher O., Schoofs, Till, Schlotz, Maike, Vanshylla, Kanika, Kreer, Christoph, Weiland, Daniela, Holtick, Udo, Scheid, Christof, Valter, Markus M., van Gils, Marit J., Sanders, Rogier W., Vehreschild, Jörg J., Cornely, Oliver A., Lehmann, Clara, Fätkenheuer, Gerd, Seaman, Michael S., Bloom, Jesse D., Bjorkman, Pamela J., Klein, Florian, Schommers, Philipp Frederik, Gruell, Henning, Abernathy, Morgan E., Tran, My-Kim, Dingens, Adam S., Gristick, Harry B., Barnes, Christopher O., Schoofs, Till, Schlotz, Maike, Vanshylla, Kanika, Kreer, Christoph, Weiland, Daniela, Holtick, Udo, Scheid, Christof, Valter, Markus M., van Gils, Marit J., Sanders, Rogier W., Vehreschild, Jörg J., Cornely, Oliver A., Lehmann, Clara, Fätkenheuer, Gerd, Seaman, Michael S., Bloom, Jesse D., Bjorkman, Pamela J., and Klein, Florian

Published
2020

199. Zn-alpha2-glycoprotein, an MHC class I-related glycoprotein regulator of adipose tissues: Modification or abrogation of ligand binding by site-directed mutagenesis

Author

Mcdermott, Lindsay C., Freel, June A., West, Anthony P., Bjorkman, Pamela J., and Keedy, Malcolm W.

Subjects
Glycoproteins -- Chemical properties, Ligand binding (Biochemistry) -- Research, Adipose tissues -- Research, Biological sciences, Chemistry
Abstract

Fluorescence-based binding assays and site-directed mutagenesis are used to demonstrate formally that the ZAG's (Zn-alpha2-glycoprotein) groove is indeed the binding site for hydrophobic ligands. The results add weight to the distinctivess of ZAG among MHC class I-like proteins in addition to providing defined binding-altered mutants for cellular signaling studies and potential medical applications.

Published
2006

200. Detection and characterization of the SARS-CoV-2 lineage B.1.526 in New York

Author

West, Anthony P., primary, Wertheim, Joel O., additional, Wang, Jade C., additional, Vasylyeva, Tetyana I., additional, Havens, Jennifer L., additional, Chowdhury, Moinuddin A., additional, Gonzalez, Edimarlyn, additional, Fang, Courtney E., additional, Di Lonardo, Steve S., additional, Hughes, Scott, additional, Rakeman, Jennifer L., additional, Lee, Henry H., additional, Barnes, Christopher O., additional, Gnanapragasam, Priyanthi N. P., additional, Yang, Zhi, additional, Gaebler, Christian, additional, Caskey, Marina, additional, Nussenzweig, Michel C., additional, Keeffe, Jennifer R., additional, and Bjorkman, Pamela J., additional

Published
2021
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