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

Wannisa Khamaikawin, Somphot Saoin, Sawitree Nangola, Koollawat Chupradit, Supachai Sakkhachornphop, Sudarat Hadpech, Nattawat Onlamoon, Aftab A. Ansari, Siddappa N. Byrareddy, Pierre Boulanger, Saw See Hong, Bruce E. Torbett, Chatchai Tayapiwatana

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Designed molecular scaffolds have been proposed as alternative therapeutic agents against HIV-1. The ankyrin repeat protein (AnkGAG 1D4) 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.

Original languageEnglish (US)
Article numbere249
Pages (from-to)e249
JournalMolecular Therapy - Nucleic Acids
Volume4
DOIs
StatePublished - Aug 25 2015

Keywords

  • Anti-HIV-1 molecular scaffolds
  • HIV-1-resistant cells
  • SHIV
  • SIV
  • designed ankyrin repeat proteins
  • designed zinc-finger proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Khamaikawin, W., Saoin, S., Nangola, S., Chupradit, K., Sakkhachornphop, S., Hadpech, S., Onlamoon, N., Ansari, A. A., Byrareddy, S. N., Boulanger, P., Hong, S. S., Torbett, B. E., & Tayapiwatana, C. (2015). Combined Antiviral Therapy Using Designed Molecular Scaffolds Targeting Two Distinct Viral Functions, HIV-1 Genome Integration and Capsid Assembly. Molecular Therapy - Nucleic Acids, 4, e249. [e249]. https://doi.org/10.1038/mtna.2015.22