HIV-1 Immune Escape and Neutralizing Antibodies : Solid Phase Proteoliposomes Containing HIV-1 Envelope Glycoproteins as Antigens and Immunogens and HIV-1 Core Envelope Glycoproteins Deficient in T-Helper Epitopes

Abstract

The HIV-1 envelope glycoproteins gp120 and gp41 mediate binding and fusion of the virus to target cells. The envelope glycoproteins are exposed on the surface of the virus as trimeric spikes and are the major targets for neutralizing antibodies. The design of envelope glycoprotein-based subunit vaccines has been frustrated by many viral immune escape mechanisms. Trimeric envelope glycoprotein formulations hold promise to overcome limitations of monomeric envelope glycoproteins as immunogens. The generation of native, trimeric envelope glycoprotein complexes, however, remains a major challenge. Here, solid-phase proteoliposomes containing native, trimeric HIV-1 envelope glycoprotein complexes that mimic the trimeric complex as it is found on the viral surface have been designed. In a comparative immunogenicity study, these proteoliposomes were shown to better elicit broadly neutralizing antibodies than gp120. A second trimeric envelope glycoprotein formulation, soluble YU2 gp140-GCN4 constructs, were also shown to better elicit broadly neutralizing antibodies in rabbits, extending a previous study in mice. These data support the hypothesis that trimeric envelope glycoprotein formulations are an advance over gp120-based immunogens. To date, only four broadly neutralizing antibodies against the HIV-1 envelope glycoproteins have been identified. Here, three novel Fab antibody fragments binding to the CD4 binding site of gp120 have been identified from phage-displayed antibody libraries with proteoliposomes. These Fab antibodies display some breadth and potency in neutralizing HIV-1. Comparison of the neutralizing activity of Fab antibodies and whole antibodies directed to the CD4 binding site suggests that these Fab antibodies may significantly gain neutralizing potency as whole antibodies. Many HIV-1 immune escape mechanisms complicate the elicitation of broadly neutralizing antibodies. Core gp120 envelope glycoproteins derived from primary isolate viruses were found to be deficient in T-helper epitopes. This finding is suggestive of yet another HIV-1 viral immune escape mechanism, the escape from recognition by CD4+ T-helper cells.