Advances in HIV-1 Envelope-Based Vaccine Development

As the sole viral protein expressed on the surface of viral particles and infected cells, the HIV-1 envelope glycoprotein is the most important target for vaccine development. Structurally defined sites of vulnerability recognized by broadly neutralizing antibodies (bNAbs) serve as major targets for vaccine design, including V1V2 apex, V3 base glycan, CD4-binding site, fusion peptide, and membrane proximal external region. Although well-established for affinity-matured antibody binding and antigenicity, these sites are not necessarily immunogenic. Three approaches have been undertaken to work around this problem: stabilizing native-like trimers, targeting bNAb germlines, and developing booster immunizations based on envelope-bNAb coevolution. With these approaches, breakthroughs have been made in vaccine-elicited neutralization gaining breadth, thus supporting certain immunogens and regimens over others. Here, from the perspectives of HIV-1 envelope and antibody genetics as well as structures, we systematically review the most recent advances in envelope-based vaccines and their remaining barriers. We also summarize lessons learned about HIV-1 envelope immunogenicity and discuss potential strategies for future development.