Combined Antiviral Therapy Using Designed Molecular Scaffolds Targeting Two Distinct Viral Functions, HIV-1 Genome Integration and Capsid Assembly

• Autori principali: Wannisa Khamaikawin (Autore), Somphot Saoin (Autore), Sawitree Nangola (Autore), Koollawat Chupradit (Autore), Supachai Sakkhachornphop (Autore), Sudarat Hadpech (Autore), Nattawat Onlamoon (Autore), Aftab A Ansari (Autore), Siddappa N Byrareddy (Autore), Pierre Boulanger (Autore), Saw-See Hong (Autore), Bruce E Torbett (Autore), Chatchai Tayapiwatana (Autore)
• Natura: Libro
• Pubblicazione: Elsevier, 2015-01-01T00:00:00Z.
• Soggetti: article
• Accesso online: Connect to this object online.

Riassunto

Designed molecular scaffolds have been proposed as alternative therapeutic agents against HIV-1. The ankyrin repeat protein (AnkGAG1D4) and the zinc finger protein (2LTRZFP) have recently been characterized as intracellular antivirals, but these molecules, used individually, do not completely block HIV-1 replication and propagation. The capsid-binder AnkGAG1D4, which inhibits HIV-1 assembly, does not prevent the genome integration of newly incoming viruses. 2LTRZFP, designed to target the 2-LTR-circle junction of HIV-1 cDNA and block HIV-1 integration, would have no antiviral effect on HIV-1-infected cells. However, simultaneous expression of these two molecules should combine the advantage of preventive and curative treatments. To test this hypothesis, the genes encoding the N-myristoylated Myr(+)AnkGAG1D4 protein and the 2LTRZFP were introduced into human T-cells, using a third-generation lentiviral vector. SupT1 cells stably expressing 2LTRZFP alone or with Myr(+)AnkGAG1D4 showed a complete resistance to HIV-1 in viral challenge. Administration of the Myr(+)AnkGAG1D4 vector to HIV-1-preinfected SupT1 cells resulted in a significant antiviral effect. Resistance to viral infection was also observed in primary human CD4+ T-cells stably expressing Myr(+)AnkGAG1D4, and challenged with HIV-1, SIVmac, or SHIV. Our data suggest that our two anti-HIV-1 molecular scaffold prototypes are promising antiviral agents for anti-HIV-1 gene therapy.

Descrizione del documento

2162-2531
10.1038/mtna.2015.22