C peptides as entry inhibitors for gene therapy.

Area of Science:

• Virology
• Gene Therapy
• Immunology

Background:

• HIV-1 fusion is mediated by the gp41 envelope glycoprotein.
• C peptides derived from gp41's C-terminal heptad repeat 2 region are potent HIV-1 fusion inhibitors.
• Gene therapy offers a novel approach to deliver therapeutic agents in vivo.

Purpose of the Study:

• To engineer and evaluate C peptides for HIV-1 gene therapy.
• To assess the efficacy of membrane-anchored (ma) and secreted (iSAVE) C peptides in preventing HIV-1 infection.
• To explore the potential of C peptide gene therapeutics as an alternative to current antiretroviral regimens.

Main Methods:

• Engineering of antiviral genes encoding membrane-anchored (ma) or secreted (iSAVE) C peptides.
• In vivo production of C peptides by genetically modified host cells.
• Testing of ma C peptides in a nonhuman primate model of AIDS and a phase I clinical trial.
• Evaluation of iSAVE C peptides for their ability to protect both modified and neighboring cells.

Main Results:

• Membrane-anchored C peptides efficiently prevent HIV-1 entry into modified cells, conferring a survival advantage.
• ma C peptides were found to be safe in a phase I clinical trial.
• Secreted C peptides protect both genetically modified and neighboring cells, suppressing virus replication.
• Both ma and iSAVE C peptides demonstrate significant potential for in vivo HIV-1 therapy.

Conclusions:

• C peptide gene therapeutics represent a promising strategy for AIDS treatment.
• These therapies can provide a strong benefit to AIDS patients.
• C peptide gene therapeutics could serve as an effective alternative to current antiretroviral drug regimens.