Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion

• Published in: Cell host & microbe Vol. 24; no. 4; pp. 579 - 592.e4
• Main Authors: Wang, Haoqing, Barnes, Christopher O., Yang, Zhi, Nussenzweig, Michel C., Bjorkman, Pamela J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.10.2018; Cell Press
• Subjects: Animals; CD4; CD4 Antigens - chemistry; CD4 Antigens - metabolism; CHO Cells; Cricetulus; cryoelectron microscopy; HEK293 Cells; HIV Envelope Protein gp120 - chemistry; HIV Envelope Protein gp120 - metabolism; HIV Envelope Protein gp41 - chemistry; HIV Envelope Protein gp41 - metabolism; HIV-1 - genetics; HIV-1 - physiology; HIV-1 envelope; Humans; Molecular Conformation; Protein Binding; Protein Conformation; Sequence Alignment; Sequence Analysis, Protein; viral membrane fusion; Virus Internalization; viral membrane fusion; CD4; HIV-1 envelope; cryoelectron microscopy
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2018.09.003

HIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and opening Env to enable gp41-mediated fusion. We present 3.54 Å and 4.06 Å cryoelectron microscopy structures of partially open soluble native-like Env trimers (SOSIPs) bound to CD4. One structure, a complex with a coreceptor-mimicking antibody that binds both CD4 and gp120, stabilizes the displaced V1V2 and reveals its structure. Comparing partially and fully open Envs with closed Envs shows that gp41 rearrangements are independent of the CD4-induced rearrangements that result in V1V2 displacement and formation of a 4-stranded bridging sheet. These findings suggest ordered conformational changes before coreceptor binding: (1) gp120 opening inducing side-chain rearrangements and a compact gp41 central helix conformation, and (2) 4-stranded bridging-sheet formation and V1V2 displacement. These analyses illuminate potential receptor-induced Env changes and inform design of therapeutics disrupting viral entry. [Display omitted] •Cryo-EM structures of HIV-1 Env trimer in CD4-bound, partially open conformation•CD4-induced conformational changes of HIV-1 Env V1V2 region•Mechanism of Env trimer opening and coreceptor binding site exposure•Structural biology models for early stages of HIV-1 Env-mediated membrane fusion HIV-1 Env undergoes conformational changes after binding to host receptor CD4 that allow coreceptor binding, resulting in fusion between host and viral membranes. Wang, Barnes et al. solved cryo-EM structures of CD4-bound Envs, revealing the order of changes involved in coreceptor binding-site exposure and the structure of the rearranged V1V2 loops.