Next-Generation Long-Lasting Soluble CD4-D1 Domains as HIV Entry Inhibitors

University of Pittsburgh researchers have engineered a next-generation soluble CD4-D1 domain with enhanced stability and extended in vivo half-life, designed to serve as a potent HIV entry inhibitor. This novel CD4-D1 variant exhibits broad HIV neutralization and avoids the immunosuppressive effects associated with traditional soluble CD4 (sCD4) treatments. This innovation could significantly advance HIV prevention strategies by providing a long-acting, highly stable, and effective HIV entry inhibitor.

Description

The primary HIV receptor, human cluster determinant 4 (CD4), has been targeted for HIV prevention through soluble CD4 (sCD4) decoys. The engineered CD4-D1 domain focuses on the D1 domain, which interacts with the HIV envelope glycoprotein (gp120). By enhancing molecular folding compactness and stability, researchers have decreased the propensity for protease degradation and eliminated binding to major histocompatibility complex class II (MHC II) peptides. This results in a CD4-D1 variant with enhanced thermostability, abrogated MHC II binding, and potent HIV neutralization. The novel CD4-D1 variant has shown extended in vivo serum half-life in mouse models, making it a promising candidate for long-acting HIV prevention.

Applications

• HIV prevention
• HIV entry inhibition
• Potential use in combination therapies for enhanced HIV treatment

Advantages

The engineered CD4-D1 variant offers several unique advantages. It eliminates MHC II binding, extending the half-life and avoiding immunosuppression. The variant also demonstrates enhanced thermostability and higher expression compared to previous sCD4, while retaining high binding to gp120 and exhibiting broad HIV neutralization. Its smaller and more stable structure reduces non-specific binding and increases accessibility to HIV epitopes, making it a potent and long-lasting HIV entry inhibitor.

Invention Readiness

The novel CD4-D1 variant has been validated through in vitro studies and mouse models, demonstrating enhanced thermostability, abrogated MHC II binding, and extended serum half-life. Ongoing research aims to further optimize the molecule and explore its potential in clinical trials. The technology is currently in the developmental stage, with promising preliminary data supporting its efficacy and stability.

IP Status

https://patents.google.com/patent/WO2025179148A1