Journal Article

Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens

Cupo, Albert, Wilson, Ian A., Sanders, Rogier W., de Taeye, Steven W., Julien, Jean-Philippe, Nieusma, Travis, Hua, Yuanzi, Yasmeen, Anila, Ozorowski, Gabriel, Klasse, P. J., Moore, John P., de la Peña, Alba Torrents, Lee, Jeong Hyun, Pugach, Pavel, Ward, Andrew B., Golabek, Michael

2015

Overview

A key challenge in the quest toward an HIV-1 vaccine is design of immunogens that can generate a broadly neutralizing antibody (bnAb) response against the enormous sequence diversity of the HIV-1 envelope glycoprotein (Env). We previously demonstrated that a recombinant, soluble, fully cleaved SOSIP.664 trimer based on the clade A BG505 sequence is a faithful antigenic and structural mimic of the native trimer in its prefusion conformation. Here, we sought clade C native-like trimers with comparable properties. We identified DU422 and ZM197M SOSIP.664 trimers as being appropriately thermostable (Tm of 63.4 °C and 62.7 °C, respectively) and predominantly native-like, as determined by negative-stain electron microscopy (EM). Size exclusion chromatography, ELISA, and surface plasmon resonance further showed that these trimers properly display epitopes for all of the major bnAb classes, including quaternary-dependent, trimer-apex (e.g., PGT145) and gp120/gp41 interface (e.g., PGT151) epitopes. A cryo-EM reconstruction of the ZM197M SOSIP.664 trimer complexed with VRC01 Fab against the CD4 binding site at subnanometer resolution revealed a striking overall similarity to its BG505 counterpart with expected local conformational differences in the gp120 V1, V2, and V4 loops. These stable clade C trimers contribute additional diversity to the pool of native-like Env immunogens as key components of strategies to induce bnAbs to HIV-1.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: Binding sites / Biological Sciences / Chromatography / Cryoelectron Microscopy / Drug Design / env Gene Products, Human Immunodeficiency Virus - chemistry / env Gene Products, Human Immunodeficiency Virus - immunology / Glycoproteins / HIV / HIV Antigens - chemistry / HIV Antigens - immunology / HIV-1 - immunology / Human immunodeficiency virus / Human immunodeficiency virus 1 / Humans / Immunoglobulin Fab Fragments - chemistry / Immunoglobulin Fab Fragments - immunology / Models, Molecular / Molecules / Negative Staining / Protein Multimerization / Protein Stability / Solubility / Temperature / Vaccines