HIV-1 Envelope Trimer Design and Immunization Strategies To Induce Broadly Neutralizing Antibodies

The identification of multiple broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) trimer has facilitated its structural characterization and guided Env immunogen design. Several recent studies constitute progress in utilizing this knowledge for the development of an HIV-1 vaccine that induces bNAbs. Native-like Env trimers can induce autologous NAb responses against resistant (Tier-2) viruses in several animal models. Here we review recent studies aimed at addressing the challenge of driving the strong but narrowly focused NAb responses to Env trimers towards ones with much greater breadth. Among strategies that merit pursuing are using multiple trimers as sequential or simultaneous immunogens, targeting the germline precursors of bNAbs, delivering sequential lineages of trimers derived from infected individuals who developed bNAbs, and presenting trimers as particulate antigens.

TrendsThe structure of the HIV-1 Env trimer has been solved by both X-ray crystallography and cryo-EM, guiding immunogen design improvements.Recombinant native-like HIV-1 Env trimers, based on the SOSIP.664 design, induce autologous Tier-2 neutralizing antibodies in rabbits and macaques.Stabilizing HIV-1 Env trimers in the closed pre-fusion state reduces their propensity to undergo reversible conformational transitions (‘breathing’), and this may be important for reducing their induction of immunodominant non-NAb responses.Knock-in mice that express specific inferred germline B cell receptors (BCRs) or the complete human germline BCR repertoire are valuable for evaluating Env immunogens.