Jessica Hsueh

All Publications

• Holes in the Glycan Shield of the Native HIV Envelope Are a Target of Trimer-Elicited Neutralizing Antibodies CELL REPORTS McCoy, L. E., van Gils, M. J., Ozorowski, G., Messmer, T., Briney, B., Voss, J. E., Kulp, D. W., Macauley, M. S., Sok, D., Pauthner, M., Menis, S., Cottrell, C. A., Torres, J. L., Hsueh, J., Schief, W. R., Wilson, I. A., Ward, A. B., Sanders, R. W., Burton, D. R. 2016; 16 (9): 2327-2338

  Abstract

  A major advance in the search for an HIV vaccine has been the development of a near-native Envelope trimer (BG505 SOSIP.664) that can induce robust autologous Tier 2 neutralization. Here, potently neutralizing monoclonal antibodies (nAbs) from rabbits immunized with BG505 SOSIP.664 are shown to recognize an immunodominant region of gp120 centered on residue 241. Residue 241 occupies a hole in the glycan defenses of the BG505 isolate, with fewer than 3% of global isolates lacking a glycan site at this position. However, at least one conserved glycan site is missing in 89% of viruses, suggesting the presence of glycan holes in most HIV isolates. Serum evidence is consistent with targeting of holes in natural infection. The immunogenic nature of breaches in the glycan shield has been under-appreciated in previous attempts to understand autologous neutralizing antibody responses and has important potential consequences for HIV vaccine design.

  View details for DOI 10.1016/j.celrep.2016.07.074

  View details for Web of Science ID 000382311300007

  View details for PubMedID 27545891

  View details for PubMedCentralID PMC5007210

• Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design PLOS PATHOGENS Jardine, J. G., Sok, D., Julien, J., Briney, B., Sarkar, A., Liang, C., Scherer, E. A., Dunand, C., Adachi, Y., Diwanji, D., Hsueh, J., Jones, M., Kalyuzhniy, O., Kubitz, M., Spencer, S., Pauthner, M., Saye-Francisco, K. L., Sesterhenn, F., Wilson, P. C., Galloway, D. M., Stanfield, R. L., Wilson, I. A., Burton, D. R., Schief, W. R. 2016; 12 (8): e1005815

  Abstract

  An optimal HIV vaccine should induce broadly neutralizing antibodies (bnAbs) that neutralize diverse viral strains and subtypes. However, potent bnAbs develop in only a small fraction of HIV-infected individuals, all contain rare features such as extensive mutation, insertions, deletions, and/or long complementarity-determining regions, and some are polyreactive, casting doubt on whether bnAbs to HIV can be reliably induced by vaccination. We engineered two potent VRC01-class bnAbs that minimized rare features. According to a quantitative features frequency analysis, the set of features for one of these minimally mutated bnAbs compared favorably with all 68 HIV bnAbs analyzed and was similar to antibodies elicited by common vaccines. This same minimally mutated bnAb lacked polyreactivity in four different assays. We then divided the minimal mutations into spatial clusters and dissected the epitope components interacting with those clusters, by mutational and crystallographic analyses coupled with neutralization assays. Finally, by synthesizing available data, we developed a working-concept boosting strategy to select the mutation clusters in a logical order following a germline-targeting prime. We have thus developed potent HIV bnAbs that may be more tractable vaccine goals compared to existing bnAbs, and we have proposed a strategy to elicit them. This reductionist approach to vaccine design, guided by antibody and antigen structure, could be applied to design candidate vaccines for other HIV bnAbs or protective Abs against other pathogens.

  View details for DOI 10.1371/journal.ppat.1005815

  View details for Web of Science ID 000383376000044

  View details for PubMedID 27560183

  View details for PubMedCentralID PMC4999182

• A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans IMMUNITY Sok, D., Pauthner, M., Briney, B., Lee, J., Saye-Francisco, K. L., Hsueh, J., Ramos, A., Le, K. M., Jones, M., Jardine, J. G., Bastidas, R., Sarkar, A., Liang, C., Shivatare, S. S., Wu, C., Schief, W. R., Wong, C., Wilson, I. A., Ward, A. B., Zhu, J., Poignard, P., Burton, D. R. 2016; 45 (1): 31-45

  Abstract

  The dense patch of high-mannose-type glycans surrounding the N332 glycan on the HIV envelope glycoprotein (Env) is targeted by multiple broadly neutralizing antibodies (bnAbs). This region is relatively conserved, implying functional importance, the origins of which are not well understood. Here we describe the isolation of new bnAbs targeting this region. Examination of these and previously described antibodies to Env revealed that four different bnAb families targeted the (324)GDIR(327) peptide stretch at the base of the gp120 V3 loop and its nearby glycans. We found that this peptide stretch constitutes part of the CCR5 co-receptor binding site, with the high-mannose patch glycans serving to camouflage it from most antibodies. GDIR-glycan bnAbs, in contrast, bound both (324)GDIR(327) peptide residues and high-mannose patch glycans, which enabled broad reactivity against diverse HIV isolates. Thus, as for the CD4 binding site, bnAb effectiveness relies on circumventing the defenses of a critical functional region on Env.

  View details for DOI 10.1016/j.immuni.2016.06.026

  View details for Web of Science ID 000380749000008

  View details for PubMedID 27438765

  View details for PubMedCentralID PMC4990068

• Recombinant HIV envelope trimer selects for quaternary-dependent antibodies targeting the trimer apex. Proceedings of the National Academy of Sciences of the United States of America Sok, D., van Gils, M. J., Pauthner, M., Julien, J. P., Saye-Francisco, K. L., Hsueh, J., Briney, B., Lee, J. H., Le, K. M., Lee, P. S., Hua, Y., Seaman, M. S., Moore, J. P., Ward, A. B., Wilson, I. A., Sanders, R. W., Burton, D. R. 2014; 111 (49): 17624-9

  Abstract

  Broadly neutralizing antibodies (bnAbs) targeting the trimer apex of HIV envelope are favored candidates for vaccine design and immunotherapy because of their great neutralization breadth and potency. However, methods of isolating bnAbs against this site have been limited by the quaternary nature of the epitope region. Here we report the use of a recombinant HIV envelope trimer, BG505 SOSIP.664 gp140, as an affinity reagent to isolate quaternary-dependent bnAbs from the peripheral blood mononuclear cells of a chronically infected donor. The newly isolated bnAbs, named "PGDM1400-1412," show a wide range of neutralization breadth and potency. One of these variants, PGDM1400, is exceptionally broad and potent with cross-clade neutralization coverage of 83% at a median IC50 of 0.003 µg/mL. Overall, our results highlight the utility of BG505 SOSIP.664 gp140 as a tool for the isolation of quaternary-dependent antibodies and reveal a mosaic of antibody responses against the trimer apex within a clonal family.

  View details for DOI 10.1073/pnas.1415789111

  View details for PubMedID 25422458

  View details for PubMedCentralID PMC4267403

• Toward a more accurate view of human B-cell repertoire by next-generation sequencing, unbiased repertoire capture and single-molecule barcoding. Scientific reports He, L., Sok, D., Azadnia, P., Hsueh, J., Landais, E., Simek, M., Koff, W. C., Poignard, P., Burton, D. R., Zhu, J. 2014; 4: 6778

  Abstract

  B-cell repertoire analysis using next-generation sequencing has become a valuable tool for interrogating the genetic record of humoral response to infection. However, key obstacles such as low throughput, short read length, high error rate, and undetermined bias of multiplex PCR method have hindered broader application of this technology. In this study, we report several technical advances in antibody repertoire sequencing. We first demonstrated the ability to sequence antibody variable domains using the Ion Torrent PGM platform. As a test case, we analyzed the PGT121 class of antibodies from IAVI donor 17, an HIV-1-infected individual. We then obtained "unbiased" antibody repertoires by sequencing the 5'-RACE PCR products of B-cell transcripts from IAVI donor 17 and two HIV-1-uninfected individuals. We also quantified the bias of previously published gene-specific primers by comparing the repertoires generated by 5'-RACE PCR and multiplex PCR. We further developed a single-molecule barcoding strategy to reduce PCR-based amplification noise. Lastly, we evaluated several new PGM technologies in the context of antibody sequencing. We expect that, based upon long-read and high-fidelity next-generation sequencing technologies, the unbiased analysis will provide a more accurate view of the overall antibody repertoire while the barcoding strategy will facilitate high-resolution analysis of individual antibody families.

  View details for DOI 10.1038/srep06778

  View details for PubMedID 25345460

  View details for PubMedCentralID PMC4894419

• A Recombinant HIV Envelope Trimer Selects for Quaternary Dependent Antibodies Targeting the Trimer Apex Sok, D., van Gils, M. J., Pauthner, M., Saye-Francisco, K. L., Hsueh, J., Briney, B., Julien, J., Lee, P. S., Hua, Y., Moore, J. P., Wilson, I. A., Sanders, R. W., Burton, D. R. MARY ANN LIEBERT, INC. 2014: A7-A8

  View details for DOI 10.1089/aid.2014.5002.abstract

  View details for Web of Science ID 000344774400004