Conformations of the Human Immunodeficiency Virus (HIV-1) Envelope Glycoproteins in Detergents and Styrene-Maleic Acid Lipid Particles (SMALPs)

作者：Rong Zhou, Shijian Zhang, Hanh T. Nguyen, Haitao Ding, Althea Gaffney, John C. Kappes, Amos B. Smith, Joseph Sodroski · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.03.01.530731 · 被引用次数：1 · 研究领域：HIV Research and Treatment、Monoclonal and Polyclonal Antibodies Research、HIV/AIDS drug development and treatment

ABSTRACT The mature human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer, which consists of non-covalently associated gp120 exterior and gp41 transmembrane subunits, mediates virus entry into cells. The pretriggered (State-1) Env conformation is the major target for broadly neutralizing antibodies (bNAbs), whereas receptor-induced downstream Env conformations elicit immunodominant, poorly neutralizing antibody (pNAb) responses. To examine the contribution of membrane anchorage to the maintenance of the metastable pretriggered Env conformation, we compared wild-type and State-1-stabilized Envs solubilized in detergents or in styrene-maleic acid (SMA) copolymers. SMA directly incorporates membrane lipids and resident membrane proteins into lipid nanodiscs (SMALPs). The integrity of the Env trimer in SMALPs was maintained at both 4°C and room temperature. By contrast, Envs solubilized in Cymal-5, a non-ionic detergent, were unstable at room temperature, although their stability was improved at 4°C and after incubation with the entry inhibitor BMS-806. Envs solubilized in ionic detergents were relatively unstable at either temperature. Comparison of Envs solubilized in Cymal-5 and SMA at 4°C revealed subtle differences in bNAb binding to the gp41 membrane-proximal external region (MPER), consistent with these distinct modes of Env solubilization. Otherwise, the antigenicity of the Cymal-5- and SMA- solubilized Envs was remarkably similar, both in the absence an...