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Background:  Viral replication relies on cellular elements that may be targeted for inhibition. Cellular deoxyhypusine hydroxylase (DOHH) enzymatically activates eukaryotic initiation of translation factor 5A (eIF5A), which has been implicated as a co-factor for HIV Rev and replication. Molecules docking into the DOHH active site and blocking function are predicted to possess antiretroviral activity. Testing this hypothesis, we investigated the drugs deferiprone (DEF), an oral agent used to treat iron overload, and ciclopirox (CPX), a topical antifungal agent, as well as the CPX analog P2, predicted by the structure-activity relation (SAR) for DOHH inhibitors to be less active or inactive.

Methods:  Compounds were assayed for inhibition of DOHH. Suppression of retroviral protein synthesis (p24) and of virion formation (RNA copy number) was measured in chronically infected H9 cells and in short- and long-term infection of freshly harvested, uninfected peripheral blood mononuclear cells (PBMC) with clinical HIV-1 isolates.

Results: DEF and CPX suppressed DOHH in vitro at distinctly lower concentrations than P2 (40 vs 170 µM). Similarly, DEF and CPX but not P2 inhibited p24 synthesis in both infected H9 cells and in short/long-term infection of PBMC with wild type HIV-1. In 18-hour H9 cell experiments, DEF-200 µM and CPX-30 µM exhibited > 50% inhibition of p24 antigen than did controls. These active compounds prevented detectable p24 antigen production in acutely infected PBMC (drug added 48 hours post-infection) and markedly suppressed p24 antigen and viral RNA production in a PBMC chronic infection model over 7 to 10 days of treatment. Proviral DNA became undetectable 12 to 24 days post treatment initiation in the PBMC chronic infection model, which includes serial addition of non-infected cells.

Conclusions:  Our results suggest that the functional relation between the posttranslational hydroxylation of eIF5As and the replication of HIV-1 can be employed to realize an antiretroviral effect. DEF and CPX may serve as pilot agents for accelerated clinical trials and for the SAR-guided synthesis of a novel class of antiretrovirals targeting cellular components.

Keywords: antiretroviral; deferiprone; ciclopirox