Targeting the N332-supersite of the HIV-1 envelope for vaccine design

Introduction: Broadly neutralizing antibodies (bNAbs) that are able to target diverse global viruses are widely believed to be crucial for an HIV-1 vaccine. Several conserved targets recognized by these antibodies have been identified on the HIV-1 envelope glycoprotein. One such target that shows particular promise for vaccination is the N332-supersite. Areas covered: This review describes the potential of the N332-supersite epitope as an immunogen design platform. We discuss the structure of the epitope and the bNAbs that target it, emphasizing their diverse modes of binding. Furthermore, the successes and limitations of recent N332-supersite immunization studies are discussed. Expert opinion: During HIV-1 infection, some of the broadest and most potent bNAbs target the N332-supersite. Furthermore, some of these antibodies require less affinity maturation than the high levels typical of many bNAbs, making these potentially more achievable vaccine targets. In addition, bNAbs bind this epitope with multiple angles of approach and glycan dependencies, perhaps increasing the probability of eliciting such responses by vaccination. Animal studies have shown that N332-supersite bNAb precursors can be activated by novel immunogens. While follow-up studies must establish whether boosting strategies can drive the maturation of bNAbs from these precursors, the development of targeted N332-supersite immunogens expands our arsenal of potential HIV-1 vaccine candidates.