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

Abstract

Introduction: The 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.

Methods: The 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.

Discussion: The 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.

Conclusions: Resolving 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.

Keywords: broadly neutralizing antibodies; reverse vaccinology 2.0; structure-based vaccine design.

Figure 1

bNAb epitopes mapped onto the three‐dimensional structure of the BG505 SOSIP.664 trimer. (a) Side and top views of the bNAbs labelled in different colours that are modelled onto an EM density map of the BG505 SOSIP.664 trimer (coloured in grey). The figure includes bNAbs recognizing eight well‐defined sites of vulnerability: PG9 and PGT145 (V2apex), PGT122 and PGT128 (N332‐glycan); PGT135 and 2G12 (OD‐glycan) both involve the N332 glycan; VRC01 (CD4bs); SF12 (silent face); PGT151, 8ANC195 and 35O22 (gp120‐gp41 interface); VRC34.01 (fusion peptide); 3BC315 (gp41); and 10E8 (MPER). Only one copy of each epitope per trimer is shown for clarity. Thus, the model does not indicate the stoichiometry of bNAb binding, only the location of the epitope. (b) Side and top views of the bNAb footprints displayed in (a). This figure is an updated version of fig. 1 from de Taeye et al., 2016 [53] (we thank Gabe Ozorowski for preparing it).

Figure 2

Amino acid substitutions that are routinely used to stabilize soluble native‐like trimers. The amino acid substitutions were modelled on the BG505 SOSIP.664 trimer (see text for details). The gp120 subunit is coloured in white and the gp41 subunit in light gray. In gp120: blue ‐ S306L, R308L, A316W, T320L, E381M and Q422L hydrophobic residues; red ‐ I201C‐A433C and A73C‐A561C disulphide bonds; green ‐ I559P, L544G, T569G and N636G stabilizing mutations; magenta ‐ adjacent residues of the R6 furin cleavage site or flexible linkers. In gp41: red ‐ A501C‐T605C disulphide bond; blue ‐ D589V, K655I, K658V and E662A hydrophobic stabilizing mutations. A more extensive list of stabilizing mutations was reviewed previously [55].

Figure 3

Sources for glycan holes found on stabilized soluble native‐like trimers. (a) Side and bottom view of the glycosylated BG505 SOSIP.664 trimer. The glycans were modelled on the crystal structure of BG505 SOSIP.664 (PDB: 5CEZ) using the Glyprot tool from Glycosciences. The missing glycans at positions 241 and 289 on gp120 are indicated in blue. Colour coding reflects the occupancy of each PNGS, similar as described in [114]. Green, full occupancy (>95%); yellow, 80% to 95%; orange, 70% to 80%; red, >60% occupancy. Lower occupancy of a PNGS results in an artificial glycan hole that can be immunogenic. (b) Bottom view of the glycosylated BG505 SOSIP.664 trimer. The removal of the trimer from the membrane creates a large immunodominant hole.