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The Structural Bioinformatics Core Section (SBIS) seeks to apply the tools of computational biology and structural bioinformatics to the design of an effective HIV-1 vaccine. Over the last few years, these tools have met with growing success when applied to a wide range of problems, including protein design, protein-structure prediction, enzyme design, and drug design. Our goal is to utilize available state-of-the-art structural bioinformatics tools, as well as to develop novel methodologies, as part of a collaborative effort—within the Vaccine Research Center, with other intramural portions of the National Institutes of Health, and extramurally—to assist in vaccine design against HIV-1 and other viruses.
The efforts of the SBIS can be divided into three areas:
- Application of computational techniques to structure-based immunogen design. Specifically, a variety of techniques can be used to focus the immune response toward target epitopes and away from undesirable, often immunoprominent, regions, through an iterative process of structure-based design, immunogenic evaluation, computational manipulation, and immunogen redesign. This process takes advantage of other skill sets resident within the Virology laboratory, specifically the ability of the Structural Biology Section to provide atomic-level details on the target epitope, and of the Vector core to evaluate immunogens. We expect this strategy of rational immunogen design to lead to the elicitation of antibodies that broadly neutralize a diverse range of HIV-1 isolates. The direct rational structure-based design of antibodies is also of interest to the SBIS.
- Efforts to enhance protein crystallization and structural analysis through the use of computational tools. The solution of crystal structures and in-depth structural analysis play a pivotal role in current efforts for rational immunogen design. Often, a significant amount of structural information exists about an important biological system (e.g., for protein subunits or from cryo-electron tomography), though the central biological target resists atomic-level structural analysis (e.g., the functional viral spike of HIV-1). Computational biology can serve as a bridge between these other sources of information and the design of appropriate crystallization constructs, to enable atomic-level analysis of a particular target. Moreover, once the structure of a particular target is determined, computational biology can assist in the analysis of the structure, to extract its full biological meaning.
- Computationally-assisted design of probes for analysis of sera and isolation of monoclonal antibodies. An understanding of the serum responses of both HIV-1-infected individuals and vaccines should assist in the development of an effective HIV-1 vaccine. Computational design can assist in the development of antigenically specific probes useful in analyzing the neutralizing activity of sera and in deciphering the HIV-1 elements recognized by both binding and neutralizing antibodies. Such an understanding provides critical in vivo feedback for the iterative structure-based improvement of immunogens.
Recent progress in the field has provided encouragement that development of a vaccine for HIV-1 is possible. By combining the power and efficiency of computation with the plethora of information encrypted in protein structures, SBIS can play a central role in the vaccine design process.
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