A novel gene therapy strategy using secreted multifunctional anti-HIV proteins to confer protection to gene-modified and unmodified target cells.

Abstract

Current human immunodeficiency virus type I (HIV) gene therapy strategies focus on rendering HIV target cells non-permissive to viral replication. However, gene-modified cells fail to accumulate in patients and the virus continues to replicate in the unmodified target cell population. We have designed lentiviral vectors encoding secreted anti-HIV proteins to protect both gene-modified and unmodified cells from infection. Soluble CD4 (sCD4), a secreted single chain variable fragment (sscFv(17b)) and a secreted fusion inhibitor (sFI(T45)) were used to target receptor binding, co-receptor binding and membrane fusion, respectively. Additionally, we designed bi- and tri-functional fusion proteins to exploit the multistep nature of HIV entry. Of the seven antiviral proteins tested, sCD4, sCD4-scFv(17b), sCD4-FI(T45) and sCD4-scFv(17b)-FI(T45) efficiently inhibited HIV entry. The neutralization potency of the bi-functional fusion proteins sCD4-scFv(17b) and sCD4-FI(T45) was superior to that of sCD4 and the Food and Drug Administration-approved fusion inhibitor T-20. In co-culture experiments, sCD4, sCD4-scFv(17b) and sCD4-FI(T45) secreted from gene-modified producer cells conferred substantial protection to unmodified peripheral blood mononuclear cells. In conclusion, continuous delivery of secreted anti-HIV proteins via gene therapy may be a promising strategy to overcome the limitations of the current treatment.

• Authors: A Falkenhagen, M Ameli, S Asad, S E Read, S Joshi
• Journal: Gene therapy (Gene Ther) Vol. 21 Issue 2 Pg. 175-87 (Feb 2014) ISSN: 1476-5462 [Electronic] England
• PMID: 24305417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antibodies, Monoclonal
• Biological Products
• CD4 Antigens
• HIV Fusion Inhibitors
• Single-Chain Antibodies

Topics

• Anti-HIV Agents (pharmacology)
• Antibodies, Monoclonal (genetics, pharmacology)
• Biological Products (pharmacology)
• CD4 Antigens (genetics, pharmacology)
• Cell Line, Tumor
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage)
• HEK293 Cells
• HIV Fusion Inhibitors (pharmacology)
• HIV-1 (drug effects)
• Humans
• Lentivirus (genetics)
• Single-Chain Antibodies (genetics, pharmacology)
• United States
• United States Food and Drug Administration