Antigenic Characteristics of Rhinovirus Chimeras Designed in silico for En5hanced Presentation of HIV-1 gp41 Epitopes

作者：Lapelosa Mauro; Arnold Gail Ferstandig^*; Gallicchio Emilio; Arnold Eddy; Levy Ronald M

来源：Journal of Molecular Biology, 2010, 397(3): 752-766.

DOI：10.1016/j.jmb.2010.01.064

• vaccine design
• monoclonal antibody 2F5
• chimeric virus
• reorganization free energy
• protein binding

The development of an effective AIDS vaccine remains the most promising long-term strategy to combat human immunodeficiency virus (HIV)/AIDS. Here, we report favorable antigenic characteristics of vaccine candidates isolated from a combinatorial library of human rhinoviruses displaying the ELDKWA epitope of the gp41 glycoprotein of HIV-1. The design principles of this library emerged from the application of molecular modeling calculations in conjunction with our knowledge of previously obtained ELDKWA-displaying chimeras, including knowledge of a chimera with one of the best 2F5-binding characteristics obtained to date. The molecular modeling calculations identified the energetic and structural factors affecting the ability of the epitope to assume conformations capable of fitting into the complementarity determining region of the ELDKWA-binding, broadly neutralizing human mAb 2F5. Individual viruses were isolated from the library following competitive immunoselection and were tested using ELISA and fluorescence quenching experiments. Dissociation constants obtained using both techniques revealed that some of the newly isolated chimeras bind 2F5 with greater affinity than previously identified chimeric rhinoviruses. Molecular dynamics simulations of two of these same chimeras confirmed that their HIV inserts were partially preorganized for binding, which is largely responsible for their corresponding gains in binding affinity. The study illustrates the utility of combining structure-based experiments with computational modeling approaches for improving the odds of selecting vaccine component designs with preferred antigenic characteristics. The results obtained also confirm the flexibility of HRV as a presentation vehicle for HIV epitopes and the potential of this platform for the development of vaccine components against AIDS.

• 出版日期2010-4-2