A glycoside analog of mammalian oligomannose formulated with a TLR4-stimulating adjuvant elicits HIV-1 cross-reactive antibodies

Jean-François Bruxelle,Ralph Pantophlet,Nino Trattnig,Paul Kosma,Tess Kirilenko,Matteo Cattin,Yiqiu Yang

doi:10.1038/s41598-021-84116-w

Abstract

The occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Here, we report on the antigenicity and immunogenicity of a CRM197-conjugate of a previously reported oligomannose mimetic. Oligomannose-specific bnAbs that are less dependent on interactions with the HIV envelope protein sequence showed strong binding to the glycoconjugates, with affinities approximating those reported for their cognate epitope. The glycoconjugate is also recognized by inferred germline precursors of oligomannose-specific bnAbs, albeit with the expected low avidity, supporting its potential as an immunogen. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. Nevertheless, these findings contribute further to understanding conditions for eliciting HIV-cross-reactive oligomannose-specific antibodies and inform on next steps for improving on the elicited response.

Highlights

The occurrence of oligomannose-specific broadly neutralizing antibodies has spurred efforts to develop immunogens that can elicit similar antibodies
Members of the oligomannose‐patch specific PGT128/130 broadly reactive HIV-neutralizing antibodies (bnAbs) family bind avidly to CRM197‐conjugated glycomimetic NIT211, with affinities approximating those reported for recombinant HIV
Taken together with the SPR analyses, these results suggest that presentation of the oligomannose mimetic at a density of 4–6 molecules per CRM197 reasonably approximates oligomannose presentation on HIV gp[120] conducive to the binding of at least the PGT128/130 family of bnAbs

Summary

Introduction

The occurrence of oligomannose-specific broadly neutralizing antibodies (bnAbs) has spurred efforts to develop immunogens that can elicit similar antibodies. Immunization of human-antibody transgenic mice revealed that only a TLR4-stimulating adjuvant formulation resulted in antibodies able to bind a panel of recombinant HIV trimers. These antibodies bound at relatively modest levels, possibly explaining their inability to neutralize HIV infectivity. We previously reported on a neoglycoside that when conjugated to BSA elicits modest levels of nAbs against select HIV strains following immunization of human-antibody transgenic r ats[5] and are working on strategies to heighten elicitation of the desired antibodies, for example by introducing distinctive bacterial c onstituents[6]. We report here on the binding interaction of oligomannosespecific bnAbs from several different families along with their inferred germline (gl) precursors, i.e., the unmutated common ancestor, to a C RM197 conjugate of our lead glycoside[5]

Methods

Results

Conclusion