Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies

Alba Torrents De La Peña,Rogier W Sanders

doi:10.1186/s12977-018-0445-y

Alba Torrents De La Peña, Rogier W Sanders

Open Access

https://doi.org/10.1186/s12977-018-0445-y

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Abstract

An effective HIV-1 vaccine probably will need to be able to induce broadly neutralizing HIV-1 antibodies (bNAbs) in order to be efficacious. The many bNAbs that have been isolated from HIV-1 infected patients illustrate that the human immune system is able to elicit this type of antibodies. The elucidation of the structure of the HIV-1 envelope glycoprotein (Env) trimer has further fueled the search for Env immunogens that induce bNAbs, but while native Env trimer mimetics are often capable of inducing strain-specific neutralizing antibodies (NAbs) against the parental virus, they have not yet induced potent bNAb responses. To improve the performance of Env trimer immunogens, researchers have studied the immune responses that Env trimers have induced in animals; they have evaluated how to best use Env trimers in various immunization regimens; and they have engineered increasingly stabilized Env trimer variants. Here, we review the different approaches that have been used to increase the stability of HIV-1 Env trimer immunogens with the aim of improving the induction of NAbs. In particular, we draw parallels between the various approaches to stabilize Env trimers and ones that have been used by nature in extremophile microorganisms in order to survive in extreme environmental conditions.

Highlights

The development of an effective and safe vaccine against HIV-1 requires a detailed understanding of the virological and immunological characteristics of HIV-1 infection
Many research groups in the HIV-1 vaccine field pursue the development of a vaccine that can induce broadly neutralizing antibodies, i.e. antibodies that can target the functional envelope glycoprotein (Env) on many different virus isolates
A focus of vaccine design is the generation of soluble Env trimer mimetics that can induce such antibodies and much progress has been made over the last few years in generating recombinant Env trimers that resemble the native Env spike

Summary

Background

The development of an effective and safe vaccine against HIV-1 requires a detailed understanding of the virological and immunological characteristics of HIV-1 infection. We describe several approaches that have been pursued in order to increase the performance of soluble Env trimer mimetics as immunogens to induce NAbs. First, we review different methods that have been used to improve the stability of HIV-1 Env trimers, including forced viral evolution, structure-based design, high throughput screening of mutant trimers and selection. The structures of all SOSIP trimers showed a highly similar trimer core, but revealed some differences in the variable loops that emanate from the core [21] Another breakthrough came with the elucidation of the cryo-EM structure of a membrane-derived JR-FL trimer that was stabilized by the bNAb PGT151, but not by SOSIP mutations [8]. De Taeye et al avoided the spontaneous exposure of the V3 loop by increasing the hydrophobic interactions within the V3 domain and between the V3 and V1V2 domains, by

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Findings

Conclusion