Abstract

Significant progress has been made in the rational design of immunogens for an HIV vaccine. Atomic-level structures of viral surface proteins in key functional states, or in complex with neutralizing antibodies, reveal important viral epitopes, providing targets for antibody elicitation. Structure-based computational methods can increase the efficiency, accuracy, and likelihood of success for immunogen design efforts. Specifically, through structural analysis, manipulation, and redesign, we expect a variety of computational techniques to be applied to generate immunogens that focus the immune response: (1) away from undesirably immuno-dominant regions; and (2) towards specific target epitopes. Such rationally designed immunogens are thus expected to enable the elicitation of broadly neutralizing antibodies capable of neutralizing a diverse range of HIV-1 isolates. We also planned to use computational algorithms to improve antibody properties, including enhancing neutralization potency and solubility, and reducing polyreactivity and immunogenicity, for therapeutic use

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Scientific Cores Intramural Research (ZIC)
Project #
1ZICAI005114-09
Application #
9781341
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Xu, Kai; Acharya, Priyamvada; Kong, Rui et al. (2018) Epitope-based vaccine design yields fusion peptide-directed antibodies that neutralize diverse strains of HIV-1. Nat Med 24:857-867
Rutten, Lucy; Lai, Yen-Ting; Blokland, Sven et al. (2018) A Universal Approach to Optimize the Folding and Stability of Prefusion-Closed HIV-1 Envelope Trimers. Cell Rep 23:584-595
Kwon, Young D; Chuang, Gwo-Yu; Zhang, Baoshan et al. (2018) Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody. Cell Rep 22:1798-1809
Dingens, Adam S; Acharya, Priyamvada; Haddox, Hugh K et al. (2018) Complete functional mapping of infection- and vaccine-elicited antibodies against the fusion peptide of HIV. PLoS Pathog 14:e1007159
Kisalu, Neville K; Idris, Azza H; Weidle, Connor et al. (2018) A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. Nat Med 24:408-416
Kwong, Peter D; Mascola, John R (2018) HIV-1 Vaccines Based on Antibody Identification, B Cell Ontogeny, and Epitope Structure. Immunity 48:855-871
Alam, S Munir; Aussedat, Baptiste; Vohra, Yusuf et al. (2017) Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide. Sci Transl Med 9:
Kwong, Peter D (2017) What Are the Most Powerful Immunogen Design Vaccine Strategies? A Structural Biologist's Perspective. Cold Spring Harb Perspect Biol :
Hwang, Joyce K; Wang, Chong; Du, Zhou et al. (2017) Sequence intrinsic somatic mutation mechanisms contribute to affinity maturation of VRC01-class HIV-1 broadly neutralizing antibodies. Proc Natl Acad Sci U S A 114:8614-8619
Zhou, Tongqing; Doria-Rose, Nicole A; Cheng, Cheng et al. (2017) Quantification of the Impact of the HIV-1-Glycan Shield on Antibody Elicitation. Cell Rep 19:719-732

Showing the most recent 10 out of 26 publications