College of Liberal Arts & Sciences

Computational Biology, Making Inroads Into AIDS Vaccine Development

Wednesday, February 1, 2012

February 1, Wed 2012
3:30 pm, Haworth 1005

Dr. Jiang Zhu

National Institute of Allergy and Infectious Diseases

Computational Biology, Making Inroads Into AIDS Vaccine Development

After several years of infection, 10-25% of HIV-1-infected individuals develop antibodies that neutralize diverse strains of HIV-1. Recently, several groups identified broadly neutralizing antibodies directed against a range of epitopes on the functional HIV-1 viral spike. Among these antibodies, those precisely targeting the CD4 binding site on the HIV-1 gp120 envelope glycoprotein are promising vaccine templates due to their remarkable breadth and potency. Structures of three VRC01-like antibodies in complex with gp120 reveal a convergent mode of binding to the CD4 binding site. To understand how these antibodies evolve to achieve precise epitope targeting and broad neutralization, we used deep sequencing to probe the antibodyome (repertoire of expressed antibodies) of HIV-1-infected individuals. With the bioinformatics tools we developed, now we can bypass the experimental isolation to identify broadly neutralizing antibodies directly from sera of HIV-1-infected individuals. Among the major epitopes on the HIV-1 viral spike, the variable regions 1 and 2 (V1/V2) of gp120 are targeted by a number of glycan-reactive antibodies, despite their extraordinary sequence diversity and N-linked glycosylation. The structure of V1/V2 in complex with PG9 revealed a “minimal” target site, comprising only one strand and two glycans. Using the scaffolding/transplantation technology, a computational procedure that grafts an epitope onto heterologous protein scaffolds, we designed 67 chimeric proteins with minimal V1V2 epitope. After experimental validation, a few epitop-scaffold proteins were found to be broadly reactive to V1V2-directed neutralizing antibodies, suggesting that they can be used as both immunogens to elicit V1V2-directed antibodies and probes for analysis of patient sera.


 

Dr. Jiang Zhu is a Staff Scientist and co-head of the Structural Bioinformatics Core Section of the Vaccine Research Center, NIAID/NIH. For more information, please visit:http://www.niaid.nih.gov/labsandresources/labs/aboutlabs/vrc/structuralbioinform/Pages/default.aspx



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