C peptides as entry inhibitors for gene therapy

Abstract

Peptides derived from the C-terminal heptad repeat 2 region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very potent HIV-1 fusion inhibitors. Antiviral genes encoding either membrane-anchored (ma) or secreted (iSAVE) C peptides have been engineered and allow direct in vivo production of the therapeutic peptides by genetically modified host cells. Membrane-anchored C peptides expressed in the HIV-1 target cells by T-cell or hematopoietic stem cell gene therapy efficiently prevent virus entry into the modified cells. Such gene-protection confers a selective survival advantage and allows accumulation of the genetically modified cells. Membrane-anchored C peptides have been successfully tested in a nonhuman primate model of AIDS and were found to be safe in a phase I clinical trial in AIDS patients transplanted with autologous gene-modified T-cells. Secreted C peptides have the crucial advantage of not only protecting genetically modified cells from HIV-1 infection, but also neighboring cells, thus suppressing virus replication even if only a small fraction of cells is genetically modified. Accordingly, various cell types can be considered as potential in vivo producer cells for iSAVEbased gene therapeutics, which could even be modified by direct in vivo gene delivery in future. In conclusion, C peptide gene therapeutics may provide a strong benefit to AIDS patients and could present an effective alternative to current antiretroviral drug regimens.