Abstract
Stabilized HIV-1 envelope glycoproteins (Env) that resemble the native Env are utilized in vaccination strategies aimed at inducing broadly neutralizing antibodies (bNAbs). To limit the exposure of rare isolate-specific antigenic residues/determinants we generated a SOSIP trimer based on a consensus sequence of all HIV-1 group M isolates (ConM). The ConM trimer displays the epitopes of most known bNAbs and several germline bNAb precursors. The crystal structure of the ConM trimer at 3.9 Å resolution resembles that of the native Env trimer and its antigenic surface displays few rare residues. The ConM trimer elicits strong NAb responses against the autologous virus in rabbits and macaques that are significantly enhanced when it is presented on ferritin nanoparticles. The dominant NAb specificity is directed against an epitope at or close to the trimer apex. Immunogens based on consensus sequences might have utility in engineering vaccines against HIV-1 and other viruses.
Highlights
Stabilized human immunodeficiency virus (HIV)-1 envelope glycoproteins (Env) that resemble the native Env are utilized in vaccination strategies aimed at inducing broadly neutralizing antibodies
This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences and such immunogens might be suitable vaccine components to prime and/or boost desirable neutralizing antibodies (NAbs) responses
Initial screening of unpurified ConM SOSIP.v4.2, SOSIP.v5.2, and SOSIP.v7 proteins from transiently transfected 293T cell supernatants showed that all constructs produced trimers, but the SOSIP.v7 construct yielded higher-quality trimers as demonstrated by more efficient binding of quaternary-dependent broadly reactive NAbs (bNAbs) PG16, PGT145, PGT151, and 35O22 in an enzyme-linked immunosorbent assay (ELISA; Supplementary Fig. 2a, b)
Summary
Stabilized HIV-1 envelope glycoproteins (Env) that resemble the native Env are utilized in vaccination strategies aimed at inducing broadly neutralizing antibodies (bNAbs). High-resolution X-ray and cryo-electron microscopic structures of BG505 SOSIP.6648 have enabled further improvement and stabilization of BG505 SOSIP trimers and facilitated the generation of SOSIP trimers from other HIV-1 strains and subtypes[9] Such trimers might not be expected to represent stand-alone vaccines, since these immunogens predominantly induced isolatespecific NAbs and sporadic and/or weak heterologous Tier 2 NAb responses at best, even when used in combination or sequential immunization regimens[10,11]. Recombinant nonnative Env protein immunogens based on consensus sequences have previously been generated[2,12,13,14,15] Such non-native immunogens are unlikely to induce NAbs against quaternary structure-dependent epitopes that are only present on the native trimer including, but not limited to, ones that target the trimer apex. This study shows that native-like HIV-1 Env trimers can be generated from consensus sequences and such immunogens might be suitable vaccine components to prime and/or boost desirable NAb responses
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