Stabilized HIV-1 envelope glycoprotein trimers for vaccine use

To provide an update on the latest developments in the field of HIV-1 antibody-based soluble envelope glycoprotein (Env) trimer design for vaccine use. The development of soluble native-like HIV-1 Env trimer immunogens has moved the field of antibody-based vaccine design forward dramatically over the past few years with refinement of various stabilizing approaches. However, despite this progress, significant challenges remain. Firstly, although trimers are relatively stable in solution, they nevertheless sample different conformational states, some of which may be less relevant to binding and induction of broadly neutralizing antibodies (bNAbs). Secondly, these trimers expose unwanted immunodominant surfaces that may distract the adaptive immune response from recognizing more immunorecessive but conserved neutralization-relevant surfaces on the trimer. The availability of atomic-resolution structural information has allowed guided design of mutations that have further stabilized trimers and allowed reduced exposure of unwanted epitopes. Moreover, chemical cross-linking approaches that do not require structural information have also contributed to trimer stabilization and selection of particular conformational forms. However, current knowledge suggests that strategies additional to trimer stabilization will be required to elicit bNAb, including targeting naive B cell receptors with specific immunogens, and guiding B cell lineages toward recognizing conserved surfaces on Env with high affinity. This review will give a perspective on these challenges, and summarize current approaches to overcoming them with the aim of developing immunogens to elicit bNAb responses in humans by active vaccination