Inhibition of Antiretroviral Drug-Resistant HIV by Pharmaceutical Interference With Cellular Hypusine Formation.

Ilona Hauber¹, Dorian Bevec², Friedrich Krätzer², Florian Horn¹, Hauke Walter³, Thomas Harrer³ and Joachim Hauber^{1 1}Heinrich-Pette-Institute for Experimental Virology and Immunology, Hamburg; ²Axxima Pharmaceuticals AG, Munich; ³University Erlangen-Nürnberg (Germany).

Background: Treatment of HIV-1-infected patients with highly active antiretroviral therapy (HAART) results in marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). However, various conventional antiretroviral drug regimens cause severe toxic side-effects in some patients on HAART, resulting in insufficient compliance and the subsequent occurence of multiple drug-resistant viruses. In order to develop advanced anti-HIV strategies we here present a novel strategy to inhibit HAART-resistant HIV. Material and Methods: By using an enzymatic assay we identified a novel small molecular weight inhibitor that blocks the essential hypusine-formation on eukaryotic initiation factor 5A (eIF-5A), which is a cellular cofactor of the HIV-1 Rev regulatory protein. Inhibitor analysis included various virus infection experiments, cell cycle and apoptosis assays and cellular toxicity studies. Results: Treatment of HIV-1-infected cells with a novel small molecular weight inhibitor that interferes with cellular hypusine-formation efficiently inhibits cytoplasmic accumulation of Rev-regulated unspliced and single-spliced viral mRNAs, and thereby virus replication. We are able to show that this type of inhibitor blocks T- and M-tropic laboratory strains, as well as primary clinical isolates. Importantly, antiretroviral drug-resistant viruses (NRTI-, NNRTI- and PI-resistant viruses), including omni-resistant isolates, are efficiently inhibited using this therapeutic strategy. Conclusion: The pharmaceutical targeting of the cellular Rev cofactor eIF-5A provides novel treatment opportunities for HIV-1-infected patients, particularly for patients that harbor viruses resistant to conventional HAART.