The Question of HIV Vaccine: Why Is a Solution Not Yet Available?

Figure 2

Schematic representation of different workflow strategies to produce new HIV-1 immunogens based on bNAbs strucure. Various antibody-based vaccination strategies have been used to develop new immunogens against HIV-1 infection. Although the techniques are numbered sequentially, there is no specific order in which they should be followed when creating novel immunogens. (1) B cell-lineage vaccine design. It involves the isolation of broad neutralizing antibodies (bNAbs) producing B cells and computationally reconstructing the whole B cell clonal lineages to replicate the molecular phylogenesis of the isolate bNAb, which will include all of its ancestral intermediates to the UCA. The ancestral intermediates and UCA act as molecular guides in immunogen development for different vaccine techniques such as germline-targeting, mutation-guided, and structure-guided immunogen design. (2) Germline targeting. Unfortunately, bNAbs UCAs cannot bind to most Env proteins, so germline targeting selects the best Env immunogen (by screening the Env variants library) that binds UCA and then uses it to construct a variety of high-affinity bNAbs precursors. The knowledge of the epitope structure can be improved using mutation-guided and structure-based immunogen design. (3) Mutation-guided immunogen design. It reflects the discovery of improbable broad neutralize mutations in ancestral intermediate bNAbs, which will be tested in an in vitro broad neutralization assay. Finally, mutated bNAbs will help to develop new immunogens. (4) Structure-based immunogen design. It consists of the atomic level characterization of the bNAbs-Env complex. It enables bioinformatic modeling of the Env immunogen around the Ab and its precursors to improve binding by introducing epitope alterations that result in the creation of the immunogen. Created with BioRender.com.