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306 Novel HIV-1 gp160 Proteoliposomes as Antigens and Immunogens
C. Grundner*1, T. Mirzabekov1,2, J. Sodroski1-3, and R. Wyatt1,2
1Dana-Farber Cancer Inst., Boston, MA, USA; 2Harvard Med. Sch., Boston, MA, USA; and 3Harvard Sch. of Publ. Hlth., Boston, MA, USA
The HIV-1 envelope glycoproteins gp120 and gp41 mediate binding and entry of virus into susceptible target cells. The envelope glycoproteins are exposed as trimeric spikes on the surface of the virus and are a major target for neutralizing antibodies. Both strain-restricted and broadly neutralizing antibodies are elicited in infected individuals. However, broadly neutralizing antibodies have been extremely difficult to elicit in vaccinated subjects. Monomeric gp120 glycoprotein elicits mostly non-neutralizing antibodies and binding of antibodies to monomeric gp120 glycoprotein does not correlate with virus neutralization. In contrast, binding of antibodies to trimeric envelope glycoproteins has been shown to correlate with neutralization of virus. Therefore, the best immunogen might be one that most faithfully mimics the trimeric envelope glycoprotein complex as found on the viral surface. We generated paramagnetic solid-phase HIV-1 gp160 proteoliposomes (PLs) containing purified, trimeric, and native envelope glycoproteins. This novel formulation retains stable envelope glycoproteins in a physiologic membrane setting. Contrary to previously described soluble envelope trimer formulations, this approach requires only minimal changes in the envelope glycoproteins. We confirmed the trimeric conformation of the envelope glycoproteins on PLs by size-exclusion chromatography, and confirmed native conformation by probing the PLs with a panel of conformationally sensitive antibodies. Due to their magnetic properties, PLs are versatile tools to identify envelope glycoprotein ligands from phage-display libraries. We have used PLs to pan phage-display libraries and have identified new envelope glycoprotein ligands. Data on immunogenicity studies will also be presented. In summary, HIV-1 gp160 solid-phase proteoliposomes represent a novel approach to faithfully mimic native, trimeric envelope glycoprotein complexes. They are valuable reagents to pan phage display libraries and hold promise as subunit candidate vaccines.
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