The HIV/AIDS pandemic emerged in the 1980s and has continued to be a major global health problem, affecting nearly 40 million people worldwide. After nearly three decades of combating the HIV/AIDS pandemic, HAART and other treatment breakthroughs have been made in controlling HIV-infection and delaying the onset of AIDS. Unfortunately, current treatment modalities, while able to suppress viral replication and reduce transmission, are unable to completely eliminate latent HIV. New promising therapies toward eradicating latent virus have emerged centered around powerful gene-editing technologies. Urgent fundamental challenge in applying these gene-editing therapies for curing HIV is how to achieve targeted delivery of the gene-editing therapy into the cytosol of all cells harboring laten HIV. We propose to explore a bacterial toxin-inspired drug delivery (BTIDD) approach to design a cargo-delivery vehicle that would specifically recognize and enter HIV-infected cells and deliver the TALEN-based gene- editing cargo across cell membranes and into the cell, where the gene-editing TALEN therapy would effectively eliminate the latent viral genes, and thereby eradicate HIV infection. This proposal will provide proof-of-concept, demonstrating that a recombinant TALEN-BTIDD fusion protein with specificity for CCR5-tropic cells can be expressed and purified from E.
coli (Aim 1) and that the TALEN-BTIDD fusion protein can enter CCR5-positive JLTRG-R5 reporter cells and deliver an anti-eGFP TALEN that then edits the eGFP reporter gene (Aim 2). The ability to demonstrate elimination of the eGFP reporter gene will lay the foundation for subsequent BTIDD-based delivery of an anti-HIV TALEN therapy targeting latent HIV genes. Results from these studies would significantly advance the field toward achieving a cure for HIV.
After nearly three decades of combating the HIV/AIDS pandemic, many breakthroughs have been made in fighting HIV-infection and delaying the onset of AIDS. However, the only way to permanently cure HIV infection is through the complete eradication of proviral DNA from all virus-harboring cells of patients. We propose to explore a bacterial toxin-inspired drug delivery (BTIDD) approach to develop a cargo-delivery vehicle that would specifically recognize HIV- infected cells and deliver a powerful, recently developed, gene-editing therapy into the cell, which would then effectively eliminate the latent viral genes and thereby cure HIV infection.
