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Annual and Interim Progress Report Summaries

Principal Investigator: Leo Stamatatos

Project: Discovery of Novel HIV Neutralizing Epitopes and Their Optimal Presentation Through Computational Design of Small Immunogens

 
Submitted September 8, 2011

Over the past 5 years our consortium worked on developing a vaccine that would elicit cross-neutralizing antibodies against HIV. Two distinct, but complementary, approaches were investigated. The first approach was based on the computational design of non-HIV proteins that are specifically engineered to express single, known, HIV neutralization epitopes (epitope scaffold approach). The second approach was based on the engineering of stable, soluble trimeric Env proteins composed distinct protomers from clades A and B (heterotrimer approach). The major focus of the ‘epitope scaffold’ approach has been on the ‘4e10 epitope’, which is a highly conserved HIV neutralization epitope and is the target of the broadly neutralizing MAb 4E10. The 4e10 epitope adopts a helical conformation and is partially embedded in the viral lipid membrane. Our recent studies indicate that 4e10-like antibodies are routinely elicited by our epitope scaffolds and that these antibodies have a similar helical binding dependency as MAb 4E10. However, despite similar binding properties with MAb 4E10, these 4e10-like antibodies do not neutralize HIV. We successfully engineered stable soluble heterotrimeric clade A/B proteins and we observed that these constructs elicit more potent anti-HIV neutralizing antibody responses in rabbits than the commonly used homotrimeric proteins. We are now following on this promising result and are performing pre-clinical evaluation on non-human primates.

 

Submitted January 25, 2011 (Interim Report)
Submitted September 1, 2010
Submitted January 28, 2010 (Interim Report)
Submitted September 15, 2009
Submitted February 1, 2009 (Interim Report)
Submitted September 2, 2008
Submitted February 1, 2008 (Interim Report)
Submitted September 4, 2007
 
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