The Computational Biology Support Component (Leader, Thomas Kepler) will be organized into two teams: one team at Duke under Thomas Kepler, and the other at Los Alamos led by Bette Korber and Alan Perelson. Independently and jointly, they will work to surmount the two roadblocks: HlV-1 diversity and the inability to induce broad neutralizing antibodies (BnAbs) to HIV-1 envelope. Both sites will be involved in and collaborate on statistical analyses and immunogen design, but each will have its own primary focus. The Duke team will focus on the analysis and modeling of affinity maturation toward protective antibody phenotypes, including the inference of clonal histories back to the unmutated common ancestor and integrated analysis of structural, phenotypic, and genetic antibody data. The Los Alamos team will focus on polyvalent and mosaic immunogen design to overcome HIV diversity and assist in modeling affinity maturation and antibody repertoire. Together, the teams will statistically evaluate all results obtained from testing of the various designs as well as perform co-evolutionary analyses of BnAbs and transmitted/founder viral sequences together with the Viral Biology SRSC. Both teams will contribute to immunogen design and the development of different approaches.
Specific Aims Aim 1. Statistical analysis of HIV broadly neutralizing antibodies (BnAb) and vaccine-induced antibody and virus evolution.
Aim 2. Computational design of vaccine antigens for the induction and maturation of protective antibody responses.

Public Health Relevance

The development of a vaccine against HIV infection remains a problem of great public concern. Researchers have learned a great deal recently about how the immune system and HIV-1 interact;sophisticated new approaches to vaccine design based on these findings are being tested. These methods call for correspondingly sophisticated computational methods, to be provided by the computational biology group.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
5UM1AI100645-03
Application #
8681341
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
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
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
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
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:
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
Ding, Shilei; Tolbert, William D; Prévost, Jérémie et al. (2016) A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability. J Virol 90:8395-409
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
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
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

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