BIOINFORMATIC ANALYSIS OF VIRUS GENOMES AND PROTEIN MODELLING IN RATIONAL VACCINE DESIGN

Project Details

Project Lead
Michael Franklin 
Project Manager
Michael Franklin 
Institution
University of Pittsburgh, Molecular Biology and Ecology  
Discipline
Microbiology, Immunology, and Virology (611) 

Abstract

Human immunodeficiency virus (HIV) is the infectious agent responsible for the Acquired Immune Deficiency Syndrome (AIDS). A vaccine against HIV will most likely require the elicitation of broadly neutralizing antibodies. In this work, I computationally designed and experimentally optimized a new class of protein antigens, termed epitope-scaffolds, aimed at eliciting 2F5 and bl2, two broadly neutralizing antibodies against HIV. Using the framework of Rosetta protein modeling software, the bound conformations of the 2F5 and bl2 epitopes are transferred to heterologous proteins. Epitope-scaffolds could subsequently be used in vivo to attempt re-elicitation of the respective broadly neutralizing antibodies they were designed to interact with. Different protein design strategies, involving both fixed and flexible backbone design, were employed to engineer complex antigens that structurally stabilize the linear epitope of 2F5, that provide contacts to the long CDR H3 loop of 2F5, or that stabilize the discontinuous epitope of bl2. In vitro evolution on the surface of yeast was used together with the computational approaches to further optimize the designed epitope-scaffolds. The methods described here are general and useful for other protein design applications such as the design of novel enzymes or protein inhibitors.

Intellectual Merit

This study proposes a decision-support tool for prioritizing vaccine initiatives through the use of mathematical optimization models. The tool will allow a panel of decision makers to assess vaccine candidates over multiple criteria with information that is both quantitative and qualitative. This assessment will be the result of a methodology that integrates Data Envelopment Analysis and the Analytic Hierarchy Process.

Broader Impacts

the decision-support tool will allow researchers and funding agencies to determine which vaccine initiatives should be: more effective, affordable, profitable, reliable, easier to use and store, and more suitable to the needs of multiple populations from diverse locations and having multiple logistic needs.

Scale of Use

We need to use computer nodes with large RAM for a week.

Results