Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity

Chuang, Gwo-Yu; Geng, Hui; Pancera, Marie; Xu, Kai; Cheng, Cheng; Acharya, Priyamvada; Chambers, Michael; Druz, Aliaksandr; Tsybovsky, Yaroslav; Wanninger, Timothy G.; Yang, Yongping; Doria-Rose, Nicole A.; Georgiev, Ivelin S.; Gorman, Jason; Joyce, M. Gordon; O'Dell, Sijy; Zhou, Tongqing; McDermott, Adrian B.; Mascola, John R.; Kwong, Peter D.

doi:10.1128/JVI.02268-16

Title: Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity

Journal Article · Wed Mar 08 00:00:00 EST 2017 · Journal of Virology

DOI:https://doi.org/10.1128/JVI.02268-16· OSTI ID:1357627

Chuang, Gwo-Yu ^[1]; Geng, Hui ^[1]; Pancera, Marie ^[1]; Xu, Kai ^[1]; Cheng, Cheng ^[1]; Acharya, Priyamvada ^[1]; Chambers, Michael ^[1]; Druz, Aliaksandr ^[1]; Tsybovsky, Yaroslav ^[2]; Wanninger, Timothy G. ^[1]; Yang, Yongping ^[1]; Doria-Rose, Nicole A. ^[1]; Georgiev, Ivelin S. ^[1]; Gorman, Jason ^[1]; Joyce, M. Gordon ^[1]; O'Dell, Sijy ^[1];

^[1]; McDermott, Adrian B. ^[1]; Mascola, John R. ^[1]; Kwong, Peter D. ^[1]

National Inst. of Health, Bethesda, MD (United States). National Institute of Allergy and Infectious Diseases (NIAID)
Frederick National Lab. for Cancer Research, Frederick, MD (United States)

The HIV-1 envelope (Env) trimer is a target for vaccine design as well as a conformational machine that facilitates virus entry by transitioning between prefusion-closed, CD4-bound, and coreceptor-bound conformations by transitioning into a postfusion state. Vaccine designers have sought to restrict the conformation of the HIV-1 Env trimer to its prefusion-closed state as this state is recognized by most broadly neutralizing, but not nonneutralizing, antibodies. We previously identified a disulfide bond, I201C-A433C (DS), which stabilizes Env in the vaccine-desired prefusion-closed state. When placed into the context of BG505 SOSIP.664, a soluble Env trimer mimic developed by Sanders, Moore, and colleagues, the engineered DS-SOSIP trimer showed reduced conformational triggering by CD4. Here, we further stabilize DS-SOSIP through a combination of structure-based design and 96-well-based expression and antigenic assessment. From 103 designs, we identified one, named DS-SOSIP.4mut, with four additional mutations at the interface of potentially mobile domains of the prefusion-closed structure. We also determined the crystal structures of DS-SOSIP.4mut at 4.1-Å resolution and of an additional DS-SOSIP.6mut variant at 4.3-Å resolution, and these confirmed the formation of engineered disulfide bonds. Notably, DS-SOSIP.4mut elicited a higher ratio of tier 2 autologous titers versus tier 1 V3-sensitive titers than BG505 SOSIP.664. DS-SOSIP.4mut also showed reduced recognition of CD4 and increased thermostability. We conclude the improved antigenicity, thermostability, and immunogenicity of DS-SOSIP.4mut suggest utility as an immunogen or a serologic probe; moreover, the specific four alterations identified here, M154, M300, M302, and L320 (4mut), can also be transferred to other HIV-1 Env trimers of interest to improve their properties.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); International AIDS Vaccine Initiative (IAVI) Neutralizing Antibody Consortium; Frederick National Laboratory for Cancer Research; Leidos Biomedical Research, Inc.; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: HHSN261200800001E; W-31-109-Eng-38

OSTI ID:: 1357627

Journal Information:: Journal of Virology, Vol. 91, Issue 10; ISSN 0022-538X

Publisher:: American Society for MicrobiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Title: Structure-Based Design of a Soluble Prefusion-Closed HIV-1 Env Trimer with Reduced CD4 Affinity and Improved Immunogenicity

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