A sequestered fusion peptide in the structure of an HIV-1 transmitted founder envelope trimer

• Published in: Nature communications 2019-02, Vol.10 (1), p.873-873, Article 873
• Main Authors: Ananthaswamy, Neeti, Fang, Qianglin, AlSalmi, Wadad, Jain, Swati, Chen, Zhenguo, Klose, Thomas, Sun, Yingyuan, Liu, Yue, Mahalingam, Marthandan, Chand, Subhash, Tovanabutra, Sodsai, Robb, Merlin L., Rossmann, Michael G., Rao, Venigalla B.
• Format: Article
• Language: English
• Subjects: 101/1; 101/28; 13/109; 147/143; 631/326/596/2116; 631/326/596/2148; 631/535/1258/1259; 692/699/255/1901; 82/16; 82/29; 82/80; 82/83; Antibodies, Neutralizing - immunology; Binding Sites, Antibody - immunology; Buried structures; CD4 antigen; Cryoelectron Microscopy; Disease transmission; env Gene Products, Human Immunodeficiency Virus - genetics; env Gene Products, Human Immunodeficiency Virus - immunology; env Gene Products, Human Immunodeficiency Virus - metabolism; HIV; HIV Antibodies - immunology; HIV Envelope Protein gp120 - metabolism; HIV Envelope Protein gp41 - metabolism; HIV-1 - immunology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Hydrophobicity; Immunoglobulin Fab Fragments - immunology; Inhibitor drugs; multidisciplinary; Peptides; Protein structure; Protein Structure, Secondary; Proteins; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; Science; Science (multidisciplinary); Trimers; Vaccines; Viral envelope proteins; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08825-7

The envelope protein of human immunodeficiency virus-1 (HIV-1) and its fusion peptide are essential for cell entry and vaccine design. Here, we describe the 3.9-Å resolution structure of an envelope protein trimer from a very early transmitted founder virus (CRF01_AE T/F100) complexed with Fab from the broadly neutralizing antibody (bNAb) 8ANC195. The overall T/F100 trimer structure is similar to other reported “closed” state prefusion trimer structures. In contrast, the fusion peptide, which is exposed to solvent in reported closed structures, is sequestered (buried) in the hydrophobic core of the T/F100 trimer. A buried conformation has previously been observed in “open” state structures formed after CD4 receptor binding. The T/F100 trimer binds poorly to bNAbs including the fusion peptide-specific bNAbs PGT151 and VRC34.01. The T/F100 structure might represent a prefusion state, intermediate between the closed and open states. These observations are relevant to mechanisms of HIV-1 transmission and vaccine design. Here, the authors present the structure of the HIV envelope (Env) protein from a transmitted founder virus and show that, while the overall structure of the Env trimer is similar to other closed trimers, the fusion peptide is buried in the hydrophobic core of the trimer, which is similar to open state trimers.