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 January 28, 2010 (Interim Report)
Our Consortium aims to develop immunogens that would elicit broad and potent anti-HIV-1 neutralizing antibody responses. We are employing two distinct, but complementary, approaches: (a) We engineer immunogens derived from the natural target of anti-HIV NAbs, the HIV Envelope glycoprotein (Env), which contains multiple neutralization epitopes; and (b) we computationally design small non-HIV proteins that express specific, known, HIV-1 neutralization epitopes.
Regarding the first approach: We developed methodologies that allow us perform rapid comparative immunogenicity analysis of diverse Envs, to identify the most promising constructs, and we are evaluating novel adjuvant formulations to identify those that optimize Env immunogenicity.
Regarding the second approach: We recently reported that our computationally designed immunogens (CDI) elicit antibody responses to one of the most conserved, but poorly immunogenic neutralization epitopes on HIV-1, the 4E10 epitope (recognized by the broadly neutralizing MAb 4E10). The antibodies elicited by our CDI fail to neutralize HIV-1 despite the fact that they recognize the 4E10 epitope in a manner which is very similar to that of MAb 4E10. Our findings suggest that neutralization of HIV through the 4E10 epitope depends not only on the proper antibody recognition of the epitope but has additional requirements.
Despite efforts by different groups over many years, the structure of the functional, trimeric, HIV Env (the target of NAbs) remains unsolved. Only structures of the extracellular domain of the HIV-1 Env (the gp120 subunit) derived from clade B isolates have been reported. This seriously limits our ‘structure-based’ immunogen design efforts. Overall we aim at solving the structure of the trimeric form of Env, but we are interested in solving the structure of Env (trimeric or monomeric) derived from non-clade B isolates, since such new information will reveal similarities and differences in the structures of Env from diverse clades . Recently, our group solved the crystal structure of a truncated clade C Env. Clade C infections are predominate world wide.