Site-Specific Glycosylation of Virion-Derived HIV-1 Env Is Mimicked by a Soluble Trimeric Immunogen
CELL REPORTS
Authors: Struwe, Weston B.; Chertova, Elena; Allen, Joel D.; Seabright, Gemma E.; Watanabe, Yasunori; Harvey, David J.; Medina-Ramirez, Max; Roser, James D.; Smith, Rodman; Westcott, David; Keele, Brandon F.; Bess, Julian W., Jr.; Sanders, Rogier W.; Lifson, Jeffrey D.; Moore, John P.; Crispin, Max
Abstract
Many broadly neutralizing antibodies (bnAbs) against HIV-1 recognize and/or penetrate the glycan shield on native, virion-associated envelope glycoprotein (Env) spikes. The same bnAbs also bind to recombinant, soluble trimeric immunogens based on the SOSIP design. While SOSIP trimers are close structural and antigenic mimics of virion Env, the extent to which their glycan structures resemble ones on infectious viruses is undefined. Here, we compare the overall glycosylation of gp120 and gp41 subunits from BG505 (clade A) virions produced in a lymphoid cell line with those from recombinant BG505 SOSIP trimers, including CHO-derived clinical grade material. We also performed detailed site-specific analyses of gp120. Glycans relevant to key bnAb epitopes are generally similar on the recombinant SOSIP and virion-derived Env proteins, although the latter do contain hotspots of elevated glycan processing. Knowledge of native versus recombinant Env glycosylation will guide vaccine design and manufacturing programs.
Envelope glycoproteins sampling states 2/3 are susceptible to ADCC by sera from HIV-1-infected individuals
VIROLOGY
Authors: Prevost, Jeremie; Richard, Jonathan; Ding, Shilei; Pacheco, Beatriz; Charlebois, Roxanne; Hahn, Beatrice H.; Kaufmann, Daniel E.; Finzi, Andres
Abstract
Recent analysis of HIV-1 envelope glycoproteins (Env) dynamics showed that the unliganded Env trimer can potentially sample three conformations: a metastable "closed" conformation (State 1), an "open" CD4-bound conformation (State 3), and an intermediate "partially open" conformation (State 2). HIV-1 evolved several mechanisms to avoid "opening" its Env in order to evade immune responses such as antibody-dependent cellular cytotoxicity (ADCC), which preferentially targets Envs in the CD4-bound conformation on the surface of infected cells. Here we took advantage of a well-characterized single-residue change in the gp120 trimer association domain to modify Env conformation and evaluate its impact on ADCC responses. We found that cells infected with viruses expressing Env stabilized in States 2/3 become highly susceptible to ADCC responses by sera from HIV-1-infected individuals. Our results indicate that the conformations spontaneously sampled by the Env trimer at the surface of infected cells has a significant impact on ADCC responses.
COA
Publication 
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