HIV-1 gp120 Inner Domain Immunogen for ADCC Response
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Solution Overview
Problem
Current HIV vaccines face challenges in eliciting non-neutralizing Fc-mediated effector responses, particularly targeting the C1/C2 region of the HIV-1 gp120 protein, which is crucial for antibody-dependent cellular cytotoxicity (ADCC) and protection against HIV infection, due to poor immunogenicity of CD4-inducible epitopes in conventional vaccines.
Innovation Solution
Development of stable protein immunogens that selectively present CD4-inducible epitopes within the C1/C2 region of the HIV-1 gp120 protein, engineered to be in a CD4-bound conformation, to induce non-neutralizing Fc-mediated effector responses without neutralization epitopes, using features like deletion of the N-terminus, engineered cysteines, and replacement of the outer domain with linkers, allowing for targeted ADCC responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional HIV vaccines are used, then neutralizing antibody responses are elicited, but non-neutralizing Fc-mediated effector responses targeting the C1/C2 region are not effectively induced
Solution Approach 1:
The gp120 protein is segmented into functional domains, with the invention specifically isolating and stabilizing the inner domain (C1/C2 regions) that contains CD4-inducible epitopes. This segmentation allows the immunogen to focus on presenting only the critical ADCC-targeting epitopes without the confounding neutralization epitopes present in full-length gp120
Solution Approach 2:
The immunogen undergoes parameter changes through engineered disulfide bonds and conformational stabilization to maintain the CD4-bound state. These parameter changes ensure the epitopes remain in the conformation recognized by ADCC-inducing antibodies, significantly improving the reliability of protective immunity
2Reliability
If immunogens present CD4-inducible epitopes in native conformation, then ADCC responses are enhanced, but structural stability and immunogen consistency deteriorate
Solution Approach 1:
The immunogen is pre-stabilized in the CD4-bound conformation through engineered disulfide bonds and structural modifications before vaccination. This preliminary action ensures that the epitopes are already in the optimal configuration for ADCC recognition, eliminating the need for conformational changes upon immune system exposure and ensuring consistent structural stability
Solution Approach 2:
The immunogen combines native gp120 inner domain sequences with engineered structural elements (disulfide bonds, stabilization motifs) to create a composite structure. This composite approach maintains the biological activity and epitope conformation while dramatically improving structural stability and resistance to degradation
Data Source
AI summary
Stable immunogens comprising portions of the inner domain (ID) of the Human Immunodeficiency Virus (HIV-1) gp120 protein are provided. These ID immunogens selectively present the gp120 C1/C2 region in its CD4-bound state within a minimal structure. These ID immunogens can be used to vaccinate subjects against infection with HIV, the causative agent of Acquired Immunodeficiency Syndrome (AIDS). The immunogens can also be used as targets in screening to identify small molecule or peptide inhibitors that block HIV-1 viral entry and attachment steps, and as probes for identifying gp120 C1/C2 region-specific antibodies.