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Review
. 2024 Aug 21;31(1):83.
doi: 10.1186/s12929-024-01073-y.

Beyond glycan barriers: non-cognate ligands and protein mimicry approaches to elicit broadly neutralizing antibodies for HIV-1

Stephen Ian Walimbwa  1 , Petr Maly  2 , Leona Raskova Kafkova  3 , Milan Raska  4   5
Affiliations
Review

Beyond glycan barriers: non-cognate ligands and protein mimicry approaches to elicit broadly neutralizing antibodies for HIV-1

Stephen Ian Walimbwa et al. J Biomed Sci. .

Abstract

Human immunodeficiency virus type 1 (HIV-1) vaccine immunogens capable of inducing broadly neutralizing antibodies (bNAbs) remain obscure. HIV-1 evades immune responses through enormous diversity and hides its conserved vulnerable epitopes on the envelope glycoprotein (Env) by displaying an extensive immunodominant glycan shield. In elite HIV-1 viremic controllers, glycan-dependent bNAbs targeting conserved Env epitopes have been isolated and are utilized as vaccine design templates. However, immunological tolerance mechanisms limit the development of these antibodies in the general population. The well characterized bNAbs monoclonal variants frequently exhibit extensive levels of somatic hypermutation, a long third heavy chain complementary determining region, or a short third light chain complementarity determining region, and some exhibit poly-reactivity to autoantigens. This review elaborates on the obstacles to engaging and manipulating the Env glycoprotein as an effective immunogen and describes an alternative reverse vaccinology approach to develop a novel category of bNAb-epitope-derived non-cognate immunogens for HIV-1 vaccine design.

Keywords: Broadly neutralizing antibodies; Combinatorial protein library; Glycans; HIV-1 vaccine; Non-cognate ligands; Protein mimicry.

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Conflict of interest statement

PM and ML hold patents for Polypeptides mimicking epitopes of broadly neutralizing antibody VRC01 (Ref: PCT/CZ2020/050066), MPER, and V3-loop (European Patent Application. Ref. No. P1888EP00) as antigens for a vaccine preventing HIV-1 infection.

Figures

Fig. 1
Fig. 1
HIV-1 Env trimer structure and the conserved epitopes targeted by broadly neutralizing antibodies (bNAbs). The Env model is based on the cryo-electron microscopy structural model of the BG505 SOSIP.664 trimer available on RSCB PDB under Acc. No. 4ZMJ
Fig. 2
Fig. 2
Development of highly complex combinatorial libraries based on protein domain scaffolds. Randomization of 11 amino-acid residues in two helices of the albumin-binding domain (ABD) in streptococcal protein G is shown in yellow. VRC01 bNAb was targeted by binders (VRA) from an ABD combinatory library with a 1014 theoretical complexity. Randomization of 12 amino-acid residues in domain 10 of the human muscle contractile protein Myomesin-1 loops L1-L3 generated a combinatorial library with a 2 × 1015 theoretical complexity. The Myomedin β sheet randomization generated a combinatorial library with a 1015 theoretical complexity. MPER bNAbs 10E8, PGT121, and PGT126 were targeted by binders MLA, MLB, and MLD respectively
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