HIV gp120 Variant with Loop Deletion Exposing CD4 Binding Site

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Solution Overview

Problem

Current HIV vaccine development faces challenges in eliciting broadly neutralizing antibodies due to the HIV-1 envelope glycoproteins' extraordinary diversity and immune evasion mechanisms, with existing immunogens failing to induce antibodies that can neutralize a broad range of HIV strains.

Innovation Solution

Targeted deletions of loops surrounding the CD4 binding site (CD4BS) on the gp120 glycoprotein are made to expose the CD4BS, enhancing antibody binding and overcoming conformational barriers, thereby improving the induction of broadly neutralizing antibodies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If loop deletions are made to expose the CD4 binding site, then antibody binding is improved, but structural integrity may be compromised

Engineering Contradiction:

Improveantibody bindingVSAvoidstructural integrity

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent removes specific loop structures (beta20-beta21 loop, beta19-beta20 loop, and beta21-alpha19 loop) from the gp120 envelope glycoprotein to expose the CD4 binding site. This extraction of obstructive elements directly improves antibody accessibility and binding to the CD4BS, resolving the contradiction by eliminating the structural barriers that previously prevented effective antibody interaction.

Inventive Principle:

Principle #2Taking out (Extraction)

2Reliability

If immunogens are designed to elicit broadly neutralizing antibodies, then protective immune response is improved, but existing immunogens fail due to HIV diversity and immune evasion

Engineering Contradiction:

Improveprotective immune responseVSAvoidHIV strain diversity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent focuses modifications on the specific local region of the gp120 protein that contains the CD4 binding site, making it more accessible to antibodies. By improving the local quality of this critical region through loop deletions, the immunogen can elicit broadly neutralizing antibodies that recognize conserved epitopes across different HIV strains, overcoming the virus's diversity and evasion mechanisms.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS9266928B2Deletion of the beta 20-21 loop in HIV GP120 exposes the CD4 binding site for improved antibody binding and antibody induction

Publication Date: 2016.02.23 THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY DEPARTMENT OF HEALTH & HUMAN SERVICES

AI summary

Disclosed herein are isolated immunogens including variant gp120 polypeptides. In an example, a variant gp120 polypeptide includes a deletion of at least 8 consecutive residues of the fourth conserved loop (C4) between residues 419 and 434 of gp120 according to HXB2 numbering. Also provided are isolated nucleic acid molecules encoding the disclosed isolated immunogens. In an example, an isolated nucleic acid molecule further includes a nucleic acid molecule encoding a hepatitis B surface antigen or a variant thereof. Compositions including the isolated immunogens including variant gp120 polypeptides are also disclosed. In some examples, a composition further includes a carrier protein, such as a hepatitis B surface antigen or a variant thereof (natural or recombinant). Viral-like particles are also provided including any of the disclosed isolated immunogens or compositions. Also disclosed are uses of these variant gp120 polypeptides and nucleic acids encoding variant polypeptides, such as to induce an immune response to HIV-1.