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

Area of Science:

• Structural Biology
• Virology
• Immunology

Background:

• HIV-1 entry relies on the Env trimer mediating membrane fusion after CD4 receptor binding.
• CD4 binding triggers conformational changes in Env, displacing V1V2 loops and enabling coreceptor engagement for fusion.
• Understanding these dynamic Env rearrangements is crucial for developing effective HIV-1 entry inhibitors.

Purpose of the Study:

• To elucidate the structural basis of HIV-1 Env conformational changes induced by CD4 binding.
• To characterize the structural dynamics of Env during the initial stages of viral entry.
• To identify potential therapeutic targets by analyzing receptor-induced Env alterations.

Main Methods:

• Cryoelectron microscopy (cryo-EM) was used to determine high-resolution structures of native-like Env trimers (SOSIPs).
• Structures were obtained for Env trimers bound to CD4, including a complex with a coreceptor-mimicking antibody.
• Comparative structural analysis of closed, partially open, and fully open Env states was performed.

Main Results:

• High-resolution cryo-EM structures revealed partially open Env trimers bound to CD4.
• A coreceptor-mimicking antibody stabilized displaced V1V2 loops, elucidating their structure.
• gp41 rearrangements were found to be independent of CD4-induced V1V2 displacement and bridging sheet formation.

Conclusions:

• HIV-1 Env undergoes ordered conformational changes upon CD4 binding, including gp120 opening and V1V2 displacement.
• These changes precede coreceptor binding and involve distinct gp41 rearrangements.
• The findings provide insights into receptor-induced Env dynamics and inform the design of novel therapeutics targeting viral entry.