The HIV-1 envelope glycoprotein: structure, function and interactions with neutralizing antibodies

Abstract

To end the AIDS pandemic, an effective vaccine is sought to prevent new infections by inducing broadly active HIV-1 neutralizing antibodies. Monoclonal neutralizing antibodies can be administered therapeutically to people living with HIV-1 and preventively to those who are uninfected and at risk. Neutralizing antibodies block viral entry into susceptible cells by targeting the HIV-1 envelope glycoprotein, which mediates entry by membrane fusion. The envelope glycoprotein evades neutralizing antibody responses by multiple means, including extreme sequence variation and a dense protective glycan shield. Despite these impediments, many broadly active neutralizing human antibodies have been isolated, typically after years of HIV-1 infection. In this Review, we describe how such antibodies target distinct epitope clusters that cumulatively now cover most of the external surface of the envelope glycoprotein. These antibodies vary in potency, in the degree to which they reduce infectivity, in mechanism of action, and in structural basis, affinity and kinetics of binding. Broadly neutralizing antibody responses have, however, so far not been elicited by immunization with envelope glycoproteins. That situation may change though with the rapid advancement of structure-guided immunogen design strategies that engage germline versions of human antibodies and guide their maturation towards greater neutralization potency and breadth.