A promising new target for the development of antiretroviral therapies to treat HIV-1 has been identified, according to a recent study published in The Journal of Clinical Investigation. At present, patients are treated with various combinations of drugs that inhibit the HIV-1 life cycle by targeting the viral proteins HIV-1 reverse transcriptase, HIV-1 protease and gp41. These drug combinations have markedly reduced death rates caused by HIV-1 infection during the past few years. However, HIV-1 can acquire resistance to all existing drugs, and the number of patients who are infected with multidrug-resistant strains is rising, limiting future treatment options. So, there is a pressing need for new anti-HIV drugs, particularly those that have a novel mechanism of action, as these might be less likely to show cross-resistance with current therapies.
Hauber and colleagues now report that blocking a host-cell factor — human deoxyhypusine synthase (DHS) — provides a successful means of preventing the replication of HIV-1, including strains that are resistant to highly active antiretroviral therapy (HAART). CNI-1493, a small molecule that is currently undergoing Phase II trials for Crohn's disease, was found to be a potent inhibitor of DHS, and therefore viral replication. Inhibition of DHS by RNA interference also showed antiviral effects in cell culture and primary cells. These authors then cultured T-cell-tropic and macrophage-tropic laboratory strains, peripheral blood mononuclear cells from patients infected with HIV-1 and a series of antiretroviral-resistant viruses in the presence of CNI-1493, which effectively suppressed viral replication, indicating that this compound would make an ideal inhibitor of drug-resistant viruses.
Normally, DHS activates eukaryotic initiation factor 5A (eIF-5A) by initiating the first of two reactions that convert inactive eIF-5A to its active hypusine-containing form. eIF-5A is involved in the metabolism of specific cellular RNAs, and is a cellular cofactor of the HIV-1 viral regulatory protein Rev, which is essential for the replication of HIV-1. Blocking DHS therefore suppresses viral replication by interfering with eIF-5A activity. Nevertheless, the precise mechanism of action of the anti-DHS activity of CNI-1493 remains to be determined.
Importantly, it seems that the action of CNI-1493 is restricted to inhibition of DHS, because there were no detrimental effects on apoptosis, cell-cycle progression and cytotoxicity, as seen in some other studies of inhibitors of eIF-5A activity, at concentrations that effectively prevented viral replication. This new work therefore supports the idea that small-molecule inhibitors of DHS could be developed as successful antiviral therapies to combat strains of HIV that are resistant to currently available drugs.
References
ORIGINAL RESEARCH PAPER
Hauber, I. et al. Identification of cellular deoxyhypusine synthase as a novel target for antiretroviral therapy. J. Clin. Invest. 115, 76–85 (2005)
FURTHER READING
De Clercq, E. Strategies in the design of antiviral drugs. Nature Rev. Drug Discov. 1, 13–25 (2002)
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Rowan, A. A step ahead of drug resistance. Nat Rev Drug Discov 4, 192 (2005). https://doi.org/10.1038/nrd1671
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DOI: https://doi.org/10.1038/nrd1671