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Exposing HIV-1 Env: Implications for therapeutic strategies
1Centre de Recherche du CHUM and Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, QC. andres.finzi@umontreal.ca.
Summary
The human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) changes shape, becoming vulnerable to immune attacks. Stabilizing its open form offers a new strategy against HIV-1 infection.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- The HIV-1 envelope glycoprotein trimer (Env) is a key target for immune responses, including neutralizing antibodies and those mediating antibody-dependent cellular cytotoxicity (ADCC).
- HIV-1 Env exists in multiple conformational states (1, 2, and 3), with a closed, antibody-resistant state (state 1) prevalent before CD4 receptor binding.
Purpose of the Study:
- To investigate the conformational dynamics of HIV-1 Env and its implications for antibody recognition and ADCC.
- To explore strategies for stabilizing open Env conformations to enhance susceptibility to ADCC.
Main Methods:
- Analysis of HIV-1 Env conformational states.
- Characterization of antibody binding to different Env conformations.
- Investigation of CD4 binding effects on Env structure and antibody interactions.
Main Results:
- CD4 binding induces an "open" Env conformation (states 2/3), increasing vulnerability to ADCC by non-neutralizing antibodies.
- Specific antibody families (anti-coreceptor binding site, anti-cluster A) and CD4-mimetic compounds can stabilize an intermediate open state (state 2A).
- This stabilized state (2A) is highly susceptible to ADCC, highlighting a potential therapeutic vulnerability.
Conclusions:
- HIV-1 Env conformational flexibility is a critical factor in immune evasion and susceptibility.
- Targeting and stabilizing open Env conformations, particularly state 2A, presents a promising interventional approach for combating HIV-1 infection via ADCC.
