An efficiently cleaved HIV-1 clade C Env selectively binds to neutralizing antibodies

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• Inducing broadly neutralizing antibodies against HIV-1 requires immunogens that mimic the native trimeric Env conformation.
• Efficient cleavage of the HIV-1 Env protein is crucial for achieving this native conformation.
• While clade B Env (JRFL) is efficiently cleaved, native clade C Env with similar properties has not been well-characterized.

Purpose of the Study:

• To identify and characterize a naturally occurring, efficiently cleaved clade C HIV-1 Env protein.
• To validate its native conformation and potential as an immunogen platform.
• To investigate the role of the cytoplasmic tail and codon optimization on Env expression and conformation.

Main Methods:

• Biochemical and antigenic characterization of the identified clade C Env (4-2.J41).
• Assessment of binding to conformation-dependent and cleavage-dependent neutralizing antibodies (e.g., PGT151).
• Analysis of the cytoplasmic tail's role in conformation and the impact of codon optimization on expression.

Main Results:

• Identification of 4-2.J41, a native clade C HIV-1 Env, that is naturally and efficiently cleaved on the cell surface.
• 4-2.J41 Env binds to conformation-dependent neutralizing antibodies and the cleavage-dependent antibody PGT151, confirming its native cleaved structure.
• The cytoplasmic tail is important for maintaining Env conformation, and codon optimization enhances expression without altering native conformation.
• 4-2.J41 Env occludes non-neutralizing epitopes.

Conclusions:

• The 4-2.J41 Env represents a significant advancement in understanding and potentially mimicking the native clade C HIV-1 Env structure.
• This efficiently cleaved Env provides a valuable platform for rational immunogen design, particularly for the prevalent clade C subtype.
• Further development of this immunogen could lead to more effective HIV-1 vaccines.