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Kevin O'Neil Saunders, PhD

Associate Professor in Surgery
Assistant Professor in the Department of Immunology
Assistant Professor in the Department of Molecular Genetics and Microbiology
Office: 2 Genome Court, 4074 Medical Science Research Building 2, Durham, NC 27710
Campus Mail: DUMC Box 3020 Med Ctr, Durham, NC 27710

The Saunders laboratory aims to understand the immunology of HIV-1 antibodies and the molecular biology of their interaction with HIV-1 envelope (Env) glycoprotein. Our overall goal is to develop protective antibody-based vaccines; therefore, the laboratory has two sections–antibody repertoire analysis and immunogen design. Our research premise is that vaccine-elicited antibodies will broadly neutralize HIV-1 if they can bind directly to the host glycans on Env. However, Env glycans are poorly immunogenic and require specific targeting by a vaccine immunogen to elicit an antibody response.

Anti-glycan HIV-1 antibody biology. The laboratory utilizes single B cell PCR to probe the antibody repertoire during natural infection and after vaccination. Using this technique we identified two monoclonal antibodies from HIV Env vaccinated macaques called DH501 and DH502 that bind directly to mannose glycans and to HIV-1 envelope (Env). We have characterized these antibodies using glycan immunoassays, antibody engineering, and x-ray crystallography to define the mechanisms of Env-glycan interaction by these antibodies. Glycan-reactive HIV antibodies are rarely elicited with HIV-1 vaccination; therefore we have studied the ontogeny of DH501 using longitudinal next generation sequencing and reversion of somatic mutations within the antibody variable regions. DH501 and DH502 antibodies are mostly found in the repertoire as IgG2 and IgM isotypes—similar to known natural glycan antibodies. Therefore we are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. The results of these studies inform us about the similarities and differences between vaccine-induced glycan-reactive antibodies and known broadly neutralizing HIV-1 antibodies from human natural infection. These comparative studies define the molecular biology of glycan-reactive antibodies as well as determine how close current vaccines are to inducing glycan-dependent broadly neutralizing antibodies.

HIV-1 Env immunogen design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. With knowledge of the antibodies we desire to elicit we can engineer the HIV-1 Env to preferentially bind to those antibodies. We discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. We translated this finding into a vaccine design strategy that we have termed “glycan learning.” This approach modifies the glycosylation of HIV-1 Env immunogens to be the optimal glycan type for engagement of the precursor antibody of glycan-reactive broadly neutralizing HIV-1 antibody lineages. The Env glycosylation sites and glycan type are then modified on subsequent Env immunogens to select antibodies that are maturing towards a broadly neutralizing phenotype. We have developed cell culture procedures and purification strategies combined with mass spectrometry analyses to create Env immunogens with specific glycosylation profiles. While the overall goal is to elicit protective neutralizing antibodies in vivo, we use these Env antigens in vitro to investigate the biology of B cell receptor engagement. More specifically, we investigate the effects of various immunogen delivery platforms, such as protein or gold nanoparticles, nucleic acid, or recombinant viral vectors on B cell activation.

Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of glycoproteins in order to produce protective vaccines.

Education and Training

  • Ph.D., Duke University, 2010

Publications

Ko, Sung-Youl, Amarendra Pegu, Rebecca S. Rudicell, Zhi-yong Yang, M Gordon Joyce, Xuejun Chen, Keyun Wang, et al. “Enhanced neonatal Fc receptor function improves protection against primate SHIV infection.” Nature 514, no. 7524 (October 30, 2014): 642–45. https://doi.org/10.1038/nature13612.

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Andersson, Ulrika, Carl Wibom, Kristina Cederquist, Steina Aradottir, Ake Borg, Georgina N. Armstrong, Sanjay Shete, et al. “Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer.” Neuro Oncol 16, no. 10 (October 2014): 1333–40. https://doi.org/10.1093/neuonc/nou052.

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Georgiev, Ivelin S., Rebecca S. Rudicell, Kevin O. Saunders, Wei Shi, Tatsiana Kirys, Krisha McKee, Sijy O’Dell, et al. “Antibodies VRC01 and 10E8 neutralize HIV-1 with high breadth and potency even with Ig-framework regions substantially reverted to germline.” J Immunol 192, no. 3 (February 1, 2014): 1100–1106. https://doi.org/10.4049/jimmunol.1302515.

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Saunders, Kevin O., Cavin Ward-Caviness, Robert J. Schutte, Stephanie A. Freel, R Glenn Overman, Nathan M. Thielman, Coleen K. Cunningham, Thomas B. Kepler, and Georgia D. Tomaras. “Secretion of MIP-1β and MIP-1α by CD8(+) T-lymphocytes correlates with HIV-1 inhibition independent of coreceptor usage.” Cell Immunol 266, no. 2 (2011): 154–64. https://doi.org/10.1016/j.cellimm.2010.09.011.

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Saunders, Kevin O., Stephanie A. Freel, R Glenn Overman, Coleen K. Cunningham, and Georgia D. Tomaras. “Epigenetic regulation of CD8(+) T-lymphocyte mediated suppression of HIV-1 replication.” Virology 405, no. 1 (September 15, 2010): 234–42. https://doi.org/10.1016/j.virol.2010.06.001.

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Freel, Stephanie A., Laurie Lamoreaux, Pratip K. Chattopadhyay, Kevin Saunders, David Zarkowsky, R Glenn Overman, Christina Ochsenbauer, et al. “Phenotypic and functional profile of HIV-inhibitory CD8 T cells elicited by natural infection and heterologous prime/boost vaccination.” J Virol 84, no. 10 (May 2010): 4998–5006. https://doi.org/10.1128/JVI.00138-10.

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Miller, Heather B., Kevin O. Saunders, Georgia D. Tomaras, and Mariano A. Garcia-Blanco. “Tat-SF1 is not required for Tat transactivation but does regulate the relative levels of unspliced and spliced HIV-1 RNAs.” Plos One 4, no. 5 (May 27, 2009): e5710. https://doi.org/10.1371/journal.pone.0005710.

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Saunders, K. O., S. A. Freel, R. Overman, C. K. Cunningham, and G. D. Tomaras. “Inhibition of histone deacetylases modulates CD8+T-lymphocyte mediated virus suppression by HIV-1 viral controllers.” In Retrovirology, Vol. 6, 2009. https://doi.org/10.1186/1742-4690-6-S3-P269.

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