Characterization of the HIV-1 membrane-proximal external region broadly neutralizing antibodies and their epitopes

Abstract

The fight against the AIDS (acquired immunodeficiency syndrome) pandemic is daunting. Despite enormous cost and intense research for the last three decades, HIV-1 (human immunodeficiency virus type 1, the causative agent of AIDS) is still spreading and lives are still lost. An HIV-1 vaccine is the only economical, safe and effective solution to end this battle. At IAVI Design & Development Lab, we pursue this goal by studying broadly neutralizing antibodies against the HIV-1 surface protein (Env). These antibodies, specifically antibodies 2F5 and 4E10 against the membrane-proximal external region (MPER), are powerful protective components of the humoral immunity that can block infection of a wide spectrum of HIV-1 variants. Better understanding of their properties, therefore, is critical for vaccine design. In the first study, I aimed to identify the criteria for efficient presentation of the HIV-1 MPER epitopes by the vesicular stomatitis virus glycoprotein (VSV G). VSV is a safe and immunogenic viral vector and the VSV G has several similar characteristics to the HIV-1 Env protein, making VSV a promising HIV-1 vaccine vector. Here, I characterized twenty chimeric VSV vectors containing a single HIV-1 epitope (2F5 or 4E10 epitope) and determined the insertion constraints for effective epitope presentation in VSV G: the epitope should be short, have specific sequence, and is located closer to the membrane. New residues essential for 4E10 antibody activity were also identified. In the second study, I investigated the neutralization mechanism of 2F5 and 4E10 antibodies in blocking virus’s endocytic entry. Using a combination of biochemical assays and imaging techniques to visualize virus-antibody interaction in live cells, I found that the HIV-1 MPER antibodies could prevent virus fusion in the endosomes. This intracellular inhibition is a rare neutralization mechanism for these HIV-1 IgGs. In conclusion, these studies provide valuable information about how the HIV-1 broadly neutralizing antibodies block virus infection and how the MPER antigens can be effectively incorporated into a replicating viral vector. This knowledge can advance research on HIV-1 vaccine designs and treatments that could hopeful put an end on this devastating viral infection.