Secreted Antiviral Entry Inhibitory (SAVE) Peptides for Gene Therapy of HIV Infection

Abstract

Gene therapeutic strategies for human immunodeficiency virus type 1 (HIV-1) infection could potentially overcome the limitations of standard antiretroviral drug therapy (ART). However, in none of the clinical gene therapy trials published to date, therapeutic levels of genetic protection have been achieved in the target cell population for HIV-1. To improve systemic antiviral efficacy, C peptides, which are efficient inhibitors of HIV-1 entry, were engineered for high-level secretion by genetically modified cells. The size restrictions for efficient peptide export through the secretory pathway were overcome by expressing the C peptides as concatemers, which were processed into monomers by furin protease cleavage. These secreted antiviral entry inhibitory (SAVE) peptides mediated a substantial protective bystander effect on neighboring nonmodified cells, thus suppressing virus replication even if only a small fraction of cells was genetically modified. Accordingly, these SAVE peptides may provide a strong benefit to AIDS patients in future, and, if applied by direct in vivo gene delivery, could present an effective alternative to antiretroviral drug regimen.

Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV

“…VRX496-T did not selectively expand in the presence of viremia, confirming mathematical modeling 16,35 and indicating that VRX496, as expected, does not protect transduced cells once they are infected. Alternative approaches may be needed, such as combination with a more potent genetic antiviral to drive selective outgrowth of cells during viremia 1,[36][37][38] or preinfusion conditioning regimens to promote homeostatic proliferation of the infused cells to enhance engraftment 39 and facilitate durable efficacy. …”

A Rationally Engineered Anti-HIV Peptide Fusion Inhibitor with Greatly Reduced Immunogenicity

“…The HIV-1 HxB2 -derived peptide C46 ( Fig. 1), which has already been used in preclinical and clinical gene therapy studies (15,(35)(36)(37), was used as a control peptide in this study.…”

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

“…Recently, promising results were obtained with the fusion inhibitor C46 (FI C46 ), which is a peptide derived from the HIV envelope (Env) glycoprotein gp41 that prevents membrane fusion. 32 Secreted neutralizing antibodies were also tested, 33,34 but their neutralization breadth was limited. 35 Clinical trials using passive transfer of these antibodies have shown emergence of resistant viruses.…”