Soluble HIV-1 Env Trimers with Base Glycans
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Solution Overview
Problem
Current approaches to developing immunogens for HIV-1 infection are hindered by the virus's ability to evade humoral recognition through various protective mechanisms, and there is a need for agents that can effectively elicit a neutralizing immune response.
Innovation Solution
The development of novel soluble HIV-1 Env ectodomain trimers that are modified to 'lock' the trimer in a prefusion closed conformation with reduced CD4 binding affinity, while retaining binding affinity for broadly neutralizing antibodies and minimizing immunodominance at the trimer's base.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If soluble HIV-1 Env ectodomain trimers are used as immunogens, then they can be administered easily and elicit immune responses, but the membrane-proximal base of the trimer becomes exposed and creates immunodominance that reduces effectiveness
Solution Approach 1:
The patent removes the transmembrane and cytoplasmic domains from the HIV-1 Env protein, creating a soluble ectodomain trimer that lacks the membrane-anchored base. This extraction eliminates the harmful immunodominance effect while preserving the immunogenic ectodomain portion.
Solution Approach 2:
The patent applies glycan modifications specifically at the base region of the soluble trimer to mask this area and reduce its immunodominance, while leaving the rest of the trimer structure unchanged to maintain its immunogenicity.
2Stability of the object's composition
If amino acid substitutions are introduced to stabilize the trimer in prefusion closed conformation, then the trimer structure is improved and antibody binding is retained, but the complexity of the protein modification increases
Solution Approach 1:
The patent introduces disulfide bonds at predetermined positions (cysteine substitutions at positions 501-605 and 201-433) to pre-stabilize the trimer in the prefusion closed conformation before immunization, ensuring the immunogen maintains its native-like structure.
Solution Approach 2:
The patent modifies specific amino acid parameters (introducing cysteine residues for disulfide bonding, proline substitutions at position 559, and methionine/leucine substitutions at positions 302, 320, and 329) to alter the structural stability and conformational preferences of the trimer.
3Stability of the object's composition
If the trimer is modified to reduce CD4 binding affinity, then the trimer retains its native conformation better, but the binding affinity for CD4 is reduced which may affect immune response
Solution Approach 1:
The patent applies modifications (proline substitution at position 559 and methionine/leucine substitutions at positions 302, 320, and 329) specifically at the CD4 binding interface to reduce affinity, while leaving the overall trimer structure and other functional regions unchanged.
Data Source
AI summary
Immunogens comprising a soluble HIV-1 Env ectodomain trimer stabilized in a prefusion closed conformation and comprising modifications to introduce N-linked glycan sequons at the membrane-proximal base of the trimer, as well as methods of their use and production are disclosed. In several implementations, the immunogen can be used to elicit an immune response to HIV-1 in a subject.