The Structural and Lineage-Based Immunogen Design Scientific Research Support Component (SRSC) has the following roles within the overall B cell immunogen development effort: (a) to acquire a detailed structural picture of the stages of affinity maturation in clonal lineages of HlV-1 protective antibodies derived and analyzed as part of the B Cell Focus and (b) to develop approaches for design of immunogens that can elicit vaccine-induced responses similar to those that have matured in chronically infected subjects with broad neutralizing antibodies. This SRSC will receive BnAb and other protective antibody unmutated ancestor (UA) and intermediate antibodies (IA) from the B Cell Focus and other SRSCs and use UAs and IAs as template for new immunogen design.
Specific Aims :
Aim 1. Determine crystal structures of critical mAb Fabs from informative clonal antibody lineages from Aims 1 and 4 of the B Cell Focus and the Computational Biology SRSC.
Aim 2. Determine crystal structures (when feasible) of selected BnAb or other protective antibody Fabs from B Cell Focus Aims 1 and 4 in complex with gp120 (or a suitable gp120 fragment) or with a gp41 peptide or similar construct.
Aim 3. Vary selected positions on gp120 (or gp41) by random mutagenesis and use the library of variants, expressed on the surfaces of individual cells, in integrative screens for antigens that bind with enhanced affinity to UAs or lineage intermediate antibodies.
Aim 4. Express Envs or their fragments that result from the screens in Aim 3.
The detailed information about antibody affinity maturation afforded by a combination of high-throughput sequence analysis and targeted 3D molecular structure determination opens up new possibilities for designing immunogens that can direct the immune system to respond in desired directions (e.g., toward broad, rather than narrow, neutralization of HIV-1 variants).
|Chen, Shuobing; Wu, Jiayi; Lu, Ying et al. (2016) Structural basis for dynamic regulation of the human 26S proteasome. Proc Natl Acad Sci U S A 113:12991-12996|
|Tian, Ming; Cheng, Cheng; Chen, Xuejun et al. (2016) Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires. Cell 166:1471-1484.e18|
|Love, Tanzy M T; Park, Sung Yong; Giorgi, Elena E et al. (2016) SPMM: estimating infection duration of multivariant HIV-1 infections. Bioinformatics 32:1308-15|
|Barton, John P; Goonetilleke, Nilu; Butler, Thomas C et al. (2016) Relative rate and location of intra-host HIV evolution to evade cellular immunity are predictable. Nat Commun 7:11660|
|Astronomo, Rena D; Santra, Sampa; Ballweber-Fleming, Lamar et al. (2016) Neutralization Takes Precedence Over IgG or IgA Isotype-related Functions in Mucosal HIV-1 Antibody-mediated Protection. EBioMedicine 14:97-111|
|Herschhorn, Alon; Ma, Xiaochu; Gu, Christopher et al. (2016) Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins. MBio 7:|
|Theiler, James; Yoon, Hyejin; Yusim, Karina et al. (2016) Epigraph: A Vaccine Design Tool Applied to an HIV Therapeutic Vaccine and a Pan-Filovirus Vaccine. Sci Rep 6:33987|
|Ding, Shilei; Tolbert, William D; PrÃ©vost, JÃ©rÃ©mie et al. (2016) A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability. J Virol 90:8395-409|
|Jeffries Jr, T L; Sacha, C R; Pollara, J et al. (2016) The function and affinity maturation of HIV-1 gp120-specific monoclonal antibodies derived from colostral B cells. Mucosal Immunol 9:414-27|
|Abdul-Jawad, Sultan; Ondondo, Beatrice; van Hateren, Andy et al. (2016) Increased Valency of Conserved-mosaic Vaccines Enhances the Breadth and Depth of Epitope Recognition. Mol Ther 24:375-84|
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