Structure‐guided envelope trimer design in HIV‐1 vaccine development: a narrative review

Abstract

IntroductionThe development of a human immunodeficiency virus 1 (HIV‐1) vaccine remains a formidable challenge. An effective vaccine likely requires the induction of broadly neutralizing antibodies (bNAbs), which likely involves the use of native‐like HIV‐1 envelope (Env) trimers at some or all stages of vaccination. Development of such trimers has been very difficult, but much progress has been made in the past decade, starting with the BG505 SOSIP trimer, elucidation of its atomic structure and implementing subsequent design iterations. This progress facilitated understanding the weaknesses of the Env trimer, fuelled structure‐guided HIV‐1 vaccine design and assisted in the development of new vaccine designs. This review summarizes the relevant literature focusing on studies using structural biology to reveal and define HIV‐1 Env sites of vulnerability; to improve Env trimers, by creating more stable versions; understanding antibody responses in preclinical vaccination studies at the atomic level; understanding the glycan shield; and to improve “on‐target” antibody responses versus “off‐target” responses.MethodsThe authors conducted a narrative review of recently published articles that made a major contribution to HIV‐1 structural biology and vaccine design efforts between the years 2000 and 2021.DiscussionThe field of structural biology is evolving at an unprecedented pace, where cryo‐electron microscopy (cryo‐EM) and X‐ray crystallography provide complementary information. Resolving protein structures is necessary for defining which Env surfaces are accessible for the immune system and can be targeted by neutralizing antibodies. Recently developed techniques, such as electron microscopy‐based polyclonal epitope mapping (EMPEM) are revolutionizing the way we are analysing immune responses and shed light on the immunodominant targets on new vaccine immunogens. Such information accelerates iterative vaccine design; for example, by reducing undesirable off‐target responses, while improving immunogens to drive the more desirable on‐target responses.ConclusionsResolving high‐resolution structures of the HIV‐1 Env trimer was instrumental in understanding and improving recombinant HIV‐1 Env trimers that mimic the structure of viral HIV‐1 Env spikes. Newly emerging techniques in structural biology are aiding vaccine design efforts and improving immunogens. The role of structural biology in HIV‐1 vaccine design has indeed become very prominent and is unlikely to diminish any time soon.

Structural dynamics reveal isolate-specific differences at neutralization epitopes on HIV Env

“…This strategy of stabilizing the pre-fusion protein structure, which is the primary target for nAbs, originated in the HIV Env SOSIP design, but has since been adopted for stabilization of pre-fusion conformations in respiratory syncytial virus ( McLellan et al., 2013 ) and SARS-CoV-2 spike trimers ( Hsieh et al., 2020a ; Wrapp et al., 2020 ) where the improvement in potent neutralization activity appears directly a result of the fixation of the pre-fusion conformations ( Sanders and Moore, 2021 ). As is now appreciated, however, in the case of a hypervariable antigenic target such as HIV Env, achieving neutralization breadth requires not only maintaining a pre-fusion conformation for the viral protein, but also training the immune system to focus on conserved epitopes while avoiding potentially immunodominant, distracting isolate-specific epitopes ( Derking and Sanders, 2021 ; D'Souza et al., 2020 ).…”

Antibodies to combat viral infections: development strategies and progress

“…Research on the development of an HIV vaccine has strongly benefited from the isolation of human bNAbs, reviewed in depth elsewhere 307 – 310 . The use of bNAb-instructed stabilization of HIV Env trimers is the basis for many promising immunogens 311 . In addition, the most promising strategies use stabilized trimers with the aims of activating particular bNAb-producing cell precursors and guiding their affinity maturation to generate mature bNAbs — a strategy called germline targeting 312 .…”

Single-component multilayered self-assembling protein nanoparticles presenting glycan-trimmed uncleaved prefusion optimized envelope trimers as HIV-1 vaccine candidates

“…While gp120-derived constructs are still promising CD4bs immunogens (14)(15)(16)(17)(18), the ongoing HIV-1 vaccine efforts have largely shifted to Env trimers, as exemplified by SOSIP (19)(20)(21)(22), native flexibly linked (NFL) (23)(24)(25), and uncleaved prefusion optimized (UFO) trimers (26)(27)(28). As the first rational trimer design, SOSIP transformed the HIV-1 vaccine field and generated a wealth of information on Env structure and immunogenicity (29). Both SOSIP and NFL are empirical designs that may require additional mutations to improve trimer stability (e.g., SOSIP.v9 (30)).…”