Soluble Prefusion Closed DS-SOSIP.664-Env Trimers of Diverse HIV-1 Strains

M. Gordon Joyce; Ivelin S. Georgiev; Yongping Yang; Aliaksandr Druz; Hui Geng; Gwo-Yu Chuang; Young Do Kwon; Marie Pancera; Reda Rawi; Mallika Sastry; Guillaume B.E. Stewart-Jones; Angela Zheng; Tongqing Zhou; Misook Choe; Joseph G. Van Galen; Rita E. Chen; Christopher R. Lees; Sandeep Narpala; Michael Chambers; Yaroslav Tsybovsky; Ulrich Baxa; Adrian B. McDermott; John R. Mascola; Peter D. Kwong

Soluble Prefusion Closed DS-SOSIP.664-Env Trimers of Diverse HIV-1 Strains

2017

Summary: The elicitation of autologous neutralizing responses by immunization with HIV-1 envelope (Env) trimers conformationally stabilized in a prefusion closed state has generated considerable interest in the HIV-1 vaccine field. However, soluble prefusion closed Env trimers have been produced from only a handful of HIV-1 strains, limiting their utility as vaccine antigens and B cell probes. Here, we report the engineering from 81 HIV-1 strains of soluble, fully cleaved, prefusion Env trimers with appropriate antigenicity. We used a 96-well expression-screening format to assess the ability of artificial disulfides and Ile559Pro substitution (DS-SOSIP) to produce soluble cleaved-Env trimers; from 180 Env strains, 20 yielded prefusion closed trimers. We also created chimeras, by utilizing structure-based design to incorporate select regions from the well-behaved BG505 strain; from 180 Env strains, 78 DS-SOSIP-stabilized chimeras, including 61 additional strains, yielded prefusion closed trimers. Structure-based design thus enables the production of prefusion closed HIV-1-Env trimers from dozens of diverse strains. : Joyce et al. use a structure-based chimeric strategy to produce prefusion closed Env trimers from 81 strains of HIV-1 encompassing all major clades. These soluble Env trimers should have utility as B cell probes and HIV-1 immunogens, thereby enabling both antibody identification and vaccine development. Keywords: conformational stabilization, envelope trimer, HIV-1 vaccine, prefusion closed trimer, structure-based design

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