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• W3203662010 abstract "The HIV-1 envelope glycoprotein (Env) trimer is responsible for viral entry into target cells and is the sole target of neutralizing antibodies. The Env protein is therefore the focus of HIV-1 vaccine design. Env consists of two noncovalently linked subunits (gp120 and gp41) that form a trimer of heterodimers and this 6-subunit complex is metastable and conformationally flexible. Several approaches have been pursued to stabilize the Env trimer for vaccine purposes, which include structure-based design, high-throughput screening, and selection by mammalian cell display. Here, we employed directed virus evolution to improve Env trimer stability. Accordingly, we deliberately destabilized the Env gp120-gp41 interface by mutagenesis in the context of replicating HIV-1 LAI virus and virus evolution over time. We identified compensatory changes that pointed at convergent evolution, as they were largely restricted to specific Env regions, namely, the V1V2 domain of gp120 and the HR1 and HR2 domain of gp41. Specifically, S614G in V1V2 and Q567R in HR1 were frequently identified. Interestingly, the majority of the compensatory mutations were at distant locations from the original mutations and most likely strengthen intersubunit interactions. These results show how the virus can overcome Env instability and illuminate the regions that play a dominant role in Env stability. IMPORTANCE A successful HIV-1 vaccine most likely requires an envelope glycoprotein (Env) component, as Env is the only viral protein on the surface of the virus and the target for neutralizing antibodies. However, HIV Env is metastable and flexible because of the weak interactions between the Env subunits, complicating the generation of recombinant mimics of native Env. Here, we used directed viral evolution to study Env stability. We deliberately destabilized the interface between Env subunits and explored the capacity of the virus to repair trimer instability by evolution. We identified compensatory mutations that converged in specific Env locations: the apex and the trimer interface. Selected mutations enhanced the stability of recombinant soluble Env trimer proteins. These results provided clues on understanding the structural mechanisms involved in Env trimer stability, which can guide future immunogen design." @default.
• W3203662010 created "2021-10-11" @default.
• W3203662010 creator A5017311188 @default.
• W3203662010 creator A5037253887 @default.
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• W3203662010 creator A5087249419 @default.
• W3203662010 creator A5087473572 @default.
• W3203662010 date "2021-09-29" @default.
• W3203662010 modified "2023-09-27" @default.
• W3203662010 title "Targeted destabilization of the HIV-1 gp120-gp41 interface leads to convergent evolution with mutations in the V1V2, HR1 and HR2 domains" @default.
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• W3203662010 doi "https://doi.org/10.1128/jvi.00532-21" @default.
• W3203662010 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34586861" @default.
• W3203662010 hasPublicationYear "2021" @default.

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