Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability

By Leopold Kong, Linling He, Natalia de Val, Nemil Vora, Charles D. Morris, P. Azadnia, D. Sok, Bin Zhou, Dennis R Burton, Andrew B. Ward and 2 more. 2016

135 citations recorded by the source corpus.

The trimeric HIV-1 envelope glycoprotein (Env) is critical for host immune recognition and neutralization. Despite advances in trimer design, the roots of Env trimer metastability remain elusive. Here we investigate the contribution of two Env regions to metastability. First, we computationally redesign a largely disordered bend in heptad region 1 (HR1) of SOSIP trimers that connects the long, central HR1 helix to the fusion peptide, substantially improving the yield of soluble, well-folded trimers. Structural and antigenic analyses of two distinct HR1 redesigns confirm that redesigned Env closely mimics the native, prefusion trimer with a more stable gp41. Next, we replace the cleavage site between gp120 and gp41 with various linkers in the context of an HR1 redesign. Electron microscopy reveals a potential fusion intermediate state for uncleaved trimers containing short but not long linkers. Together, these results outline a general approach for stabilization of Env trimers from diverse HIV-1 strains. A major goal of HIV-1 vaccine development is to produce antigens that can induce broadly neutralizing antibodies. Here the authors examine the underlying causes of HIV-1 envelope metastability and design uncleaved, prefusion-optimized gp140 trimers with potential for use as HIV-1 vaccine antigens.

Subfields: Ecology, Molecular Biology, Virology

Citations in the corpus

• DockQ: A Quality Measure for Protein-Protein Docking Models (2016, neutral): “Multimeric biological assemblies of higher order than that of dimers are also found to occur, particularly common in viral enve-lopes / capsids [23], viral glycoproteins [24,25] and cytoplasmic subunits of voltage-gated channels [26].”
• Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen (2017, unknown): “The S1/S2 furin site (RSVR), which remains uncleaved in our construct due to mutagenesis (ASVG), is located on an accessible solvent-exposed loop that is disordered in our structures (Fig.”
• Presenting native-like trimeric HIV-1 antigens with self-assembling nanoparticles (2016, unknown): “Our analyses thus revealed salient features of gp140-FR nano-particles with a redesigned HR1 bend 43 .”