Distinct allosteric remodeling of HIV-1 Env dynamics on virions by gp41-directed antibodies reveals two modes of neutralization
HIV-1 envelope glycoprotein (Env), a gp120–gp41 trimer, undergoes coordinated conformational changes that drive membrane fusion and allow immune evasion by transiently concealing neutralization-sensitive epitopes. Most broadly neutralizing antibodies (bNAbs) target gp120, whereas a distinct subset recognizes conserved gp41 regions, such as the fusion peptide and the membrane-proximal external…
HIV-1 envelope glycoprotein, a gp120-gp41 trimer, undergoes conformational shifts to allow membrane fusion and evade the immune system by temporarily hiding vulnerable sites. Broadly neutralizing antibodies generally focus on gp120, while a smaller group targets gp41 regions like the fusion peptide and external membrane region. However, the influence of these antibodies on Env dynamics and neutralization processes is still uncertain.
By employing bioorthogonal tagging for single-molecule FRET, researchers were able to observe real-time changes induced by broad neutralizing antibodies (bNAbs) on Env within intact virions. The majority of gp41-targeted bNAbs worked together to stabilize the prefusion-closed (PC) state, while a specific bivalent antibody, 10E8.4/iMab, boosted both the PC and CD4-bound open states. These antibodies altered the conformational distribution of Env only slightly, maintaining a step-by-step transition sequence.
These results shed light on two distinct neutralization modes for gp41-targeted antibodies. In each scenario, the antibodies manage to fix the PC conformation or open it up through long-range allosteric control of Env dynamics, ultimately leading to successful neutralization.
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