Conformational flexibility of HIV-1 envelope glycoproteins modulates transmitted/founder sensitivity to broadly neutralizing antibodies

Durgadevi Parthasarathy, Karunakar Reddy Pothula, Sneha Ratnapriya, Héctor Cervera Benet, Ruth Parsons, Xiao Huang, Salam Sammour, Katarzyna Janowska, Miranda Harris, Joseph Sodroski, Priyamvada Acharya and Alon Herschhorn ()
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Durgadevi Parthasarathy: University of Minnesota
Karunakar Reddy Pothula: Duke University
Sneha Ratnapriya: University of Minnesota
Héctor Cervera Benet: University of Minnesota
Ruth Parsons: Duke University
Xiao Huang: Duke University
Salam Sammour: Duke University
Katarzyna Janowska: Duke University
Miranda Harris: University of Minnesota
Joseph Sodroski: Dana-Farber Cancer Institute
Priyamvada Acharya: Duke University
Alon Herschhorn: University of Minnesota

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract HIV-1 envelope glycoproteins (Envs) of most primary HIV-1 strains exist in closed conformation and infrequently sample open states, limiting access to internal epitopes. Thus, immunogen design aims to mimic the closed Env conformation as preferred target for eliciting broadly neutralizing antibodies (bnAbs). Here we identify incompletely closed Env conformations of 6 out of 13 transmitted/founder (T/F) strains that are sensitive to antibodies that recognize internal epitopes typically exposed on open Envs. A 3.6 Å cryo-electron microscopy structure of unliganded, incompletely closed T/F Envs (1059-SOSIP) reveals protomer motion that increased sampling of states with incompletely closed trimer apex. We reconstruct de novo the post-transmission evolutionary pathway of a second T/F. Evolved viruses exhibit increased Env resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial.

Date: 2024
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DOI: 10.1038/s41467-024-51656-4

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