Antigenic analysis of the HIV-1 envelope trimer implies small differences between structural states 1 and 2

Area of Science:

• Virology
• Structural Biology
• Immunology

Background:

• The human immunodeficiency virus type 1 (HIV-1) envelope trimer (Env) is crucial for viral entry and a key target for broadly neutralizing antibodies (bnAbs).
• Single-molecule Förster resonance energy transfer (smFRET) has identified at least three distinct conformational states of HIV-1 Env on virions.
• Most bnAbs elicited during natural infection preferentially bind to State 1, a prevalent prefusion conformation, while high-resolution structures exist for States 2 and 3, but not State 1.

Purpose of the Study:

• To investigate the structural characteristics of HIV-1 Env in State 1, which remains structurally uncharacterized.
• To delineate antigenic differences between the smFRET-defined conformational states of HIV-1 Env.
• To correlate observed antigenic differences with known structural variations between Env States 2 and 3.

Main Methods:

• Enrichment of specific HIV-1 Env conformational states (States 1, 2, and 3) on cell surfaces using antibody fragments or small-molecule inhibitors.
• Assessment of binding affinities of various HIV-1 bnAbs to Env states enriched for specific conformations.
• Utilizing smFRET to define and differentiate conformational states of the HIV-1 Env trimer.

Main Results:

• Consistent, albeit small, differences in bnAb binding were observed between Env enriched in States 1 and 2.
• A greater than 10-fold difference in bnAb binding was detected between Env in States 1/2 compared to Env in State 3.
• These findings suggest substantial structural divergence between HIV-1 Env States 1 and 3.

Conclusions:

• The structural differences between HIV-1 Env States 1 and 3 are significantly larger than those between States 1 and 2.
• This study provides critical insights into the structural basis of State 1, informing the design of immunogens and therapeutic antibodies.
• Understanding Env conformational dynamics is essential for developing effective HIV-1 vaccines and treatments.