UC Santa Cruz

After over 35 years of research, a prophylactic HIV vaccine remains elusive. However, the discovery of potent broadly neutralizing antibodies (bNAbs) in some individuals (elite neutralizers) and other individuals that control HIV infection without anti-retroviral drugs (controllers) have renewed optimism that an effective vaccine may be possible. The production of bNAbs does not correlate with improved disease outcomes because they take too long to develop and the virus typically outpaces the antibody response. However, passive transfer of bNAbs prior to infection is protective in non-human primate models. Thus, a vaccine capable of eliciting bNAbs prior to infection may provide protective immunity. The sole target of bNAbs is the viral spike, a trimer of envelope glycoproteins (Env). Although it is now possible to produce recombinant Envs with epitopes that bind bNAbs, these have failed to elicit bNAbs. Epitopes recognized by bNAbs are inherently poor immunogens due to the densely packed glycan shield that covers the majority of the surface. Previous HIV vaccines were based on Envs without regard for the immune response in virus donors. Here, for the first time, we studied Envs from two rare individuals that controlled viral load and produced bNAbs. From each individual, envs were cloned and used to construct 20 pseudotype viruses. These were then screened for neutralization sensitivity against a panel of prototypic monoclonal bNAbs. Comparative sequence analysis revealed two features that may have contributed to the robust immune response: (1) a major reduction (35%) in the number of potential N-linked glycosylation sites in gp120 and (2) two extra cysteine residues in the V1/V2 region. One env from each individual was expressed and used for antibody binding assays and rabbit immunization studies. Antibody responses to the novel immunogens were compared to MN rgp120, used in the only clinical trials that has shown efficacy in humans. A minimally glycosylated immunogen elicited an improved cross-reactive neutralization response compared to other clade B Envs, including MN. This work demonstrated that Envs from individuals with the elite neutralizer/controller phenotype possess unusual structural features that may have enhanced the immune response and represent a new source of HIV vaccine immunogens.