HIV-1 gp41 Pre-Hairpin Polypeptide for Neutralizing Antibody Induction
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Solution Overview
Problem
Current HIV-1 vaccines face challenges in inducing broadly neutralizing antibodies due to the immune system's focus on non-neutralizing antibodies that target the post-fusion conformation of gp41, which is ineffective in blocking infection, as these antibodies are induced by gp41 antigens in a triggered, post-fusion form and can distract the immune response.
Innovation Solution
Development of an antigenic polypeptide mimicking the pre-hairpin intermediate conformation of gp41, including an oligomerization domain, heptad repeat 2 motif, and membrane-proximal external region, which elicits production of broadly neutralizing antibodies while avoiding the induction of non-neutralizing cluster II antibodies, thereby targeting a critical fusion-intermediate state for neutralization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gp41 antigens are presented in a triggered, post-fusion form, then the immune system generates strong antibody responses, but these antibodies are non-neutralizing and ineffective in blocking infection
Solution Approach 1:
The patent changes the conformational state parameter of gp41 from post-fusion to pre-hairpin intermediate form. This parameter change fundamentally alters the epitope landscape, causing the immune system to generate neutralizing antibodies against the pre-hairpin conformation that can block fusion, rather than non-neutralizing antibodies against the post-fusion form
Solution Approach 2:
Instead of presenting the naturally dominant post-fusion conformation that induces non-neutralizing antibodies, the patent inverts the approach by stabilizing and presenting the pre-hairpin intermediate conformation. This inversion redirects the immune response toward neutralizing epitopes that are normally occluded or transient
2Reliability
If gp41 antigens are presented in pre-fusion conformation, then neutralizing antibodies can be elicited, but the conformation is metastable and difficult to maintain
Solution Approach 1:
The patent introduces a stabilizing domain as an intermediary element that mediates between the metastable pre-fusion gp41 and the need for conformational stability. This stabilizing domain acts as a molecular scaffold that locks gp41 in the pre-hairpin intermediate conformation, preventing spontaneous transition to the post-fusion state while preserving neutralizing epitopes
Solution Approach 2:
The patent creates a composite antigen structure combining gp41 with a stabilizing domain. This composite material integrates the immunogenic properties of gp41 with the structural stability of the stabilizing domain, resulting in a chimeric molecule that maintains the pre-hairpin conformation reliably for vaccine application
3Productivity
If the immune system targets the post-fusion conformation of gp41, then abundant antibodies are produced, but these antibodies cannot block viral entry
Solution Approach 1:
The patent applies preliminary action by presenting the pre-hairpin intermediate conformation before the fusion process completes. This timing allows neutralizing antibodies to bind to gp41 in its pre-hairpin state, preventing the subsequent formation of the post-fusion conformation and blocking viral entry before it can occur
Data Source
AI summary
Isolated, antigenic polypeptides including a pre-hairpin intermediate conformation of gp41 and vectors encoding such polypeptides are provided. Exemplary pre-hairpin intermediate conformations of gp41 include an oligomerization domain; a heptad repeat 2 motif; and a membrane-proximal external region, where the polypeptide lacks a heptad repeat 1 motif, and where the isolated, antigenic polypeptides elicit production of a broadly neutralizing antibody against HIV when injected into a subject. Antibodies that bind to a pre-hairpin intermediate conformation of gp41 and methods of making antibodies a that bind to pre-hairpin intermediate conformation of gp41 are also provided. Vaccines against a pre-hairpin intermediate conformation of gp41, as well as methods of treating subjects infected with HIV, preventing HIV infection, and inhibiting HIV-mediated activities are also provided. Methods of screening compounds that bind to an isolated, pre-hairpin intermediate conformation of gp41 are further provided.