[PDF, Supplementary Information]
PDF/Online at Nature Website.
Outsmarting HIV With Vaccine Antigens Made to Order, Duke News (2015).
Summary. HIV type 1 (HIV-1) uses multiple mechanisms to evade the immune system, and these have stymied the development of an effective vaccine. One mechanism--conformational masking--hides the vulnerable shape of the spike of the trimeric envelope (Env) recognized by broadly neutralizing antibodies via structural rearrangements that expose immunodominant epitopes recognized by non-neutralizing or poorly neutralizing ("ineffective") antibodies. The upshot is that virus infection and Env immunization both elicit abundant production of Env-directed antibodies with little neutralization capacity. A potential solution is to determine the structure of the vulnerable Env conformation and to use this structural information and protein design to stabilize or to fix the vulnerable shape. The ligand-free Env trimer fixed in the prefusion closed conformation may be an ideal HIV-1 antigen.
As the sole viral antigen on the HIV-1 virion surface, trimeric Env is a focus of vaccine efforts. Here we present the structure of the ligand-free HIV-1 Env trimer, fix its conformation and determine its receptor interactions. Epitope analyses revealed trimeric ligand-free Env to be structurally compatible with broadly neutralizing antibodies but not poorly neutralizing ones. We coupled these compatibility considerations with binding antigenicity to engineer conformationally fixed Envs, including a 201C-433C (DS) variant specifically recognized by broadly neutralizing antibodies. DS-Env retained nanomolar affinity for the CD4 receptor, with which it formed an asymmetric intermediate: a closed trimer bound by a single CD4 without the typical antigenic hallmarks of CD4 induction. Antigenicity-guided structural design can thus be used both to delineate mechanism and to fix conformation, with DS-Env trimers in virus-like-particle and soluble formats providing a new generation of vaccine antigens.