Deoxyhypusine synthase: a new target for HIV therapy?

An inhibitor of the enzyme deoxyhypusine synthase (DHS) can suppress the replication of HIV, according to a test tube study presented in the January edition of The Journal of Clinical Investigation. The experimental drug CNI-1493, which is already being tested for Crohn’s disease, is active against various strains of HIV, including ones resistant to currently available HIV drugs.

DHS is a protein found in human cells that controls the production of the amino acid hypusine, one of the ‘building blocks’ of protein molecules. The only protein known to contain hypusine is eukaryotic initiation factor 5A (eIF-5A), which is necessary for the production of new HIV particles through an interaction with the HIV protein Rev.

By blocking the activity of DHS, CNI-1493 stops the production of functional eIF-5A. This in turn prevents HIV from reproducing within human cells.

“The development of…compounds that inhibit DHS appears to be a promising approach to providing novel antiretroviral therapies,” state the researchers. “Such regimens may be advantageous in salvage therapies by achieving suppression of otherwise drug-resistant viruses.”

However, further studies are required to determine whether these test tube findings will be reflected in antiretroviral activity in HIV-positive patients.

The investigators, from Hamburg and Erlangen in Germany, tested the activity of the DHS inhibitor CNI-1493 by applying it to cultures of cells infected with various strains of HIV. These included a strain that preferentially infects T-cells, as well as one that infects macrophages. After treatment for six to twelve days, “CNI-1493 blocked both the macrophage-tropic strain BaL and the T-cell-tropic strain NL4/3 very efficiently, reaching virus inhibition rates that ranged from 82% to 98%.”

Similar results were seen using virus and white blood cells isolated from four HIV-positive patients. In HIV isolated from a further patient, inhibition of viral replication was maintained for ten weeks. This “clearly demonstrated extended periods of inhibition of virus replication with no apparent loss of drug sensitivity.”

The researchers also examined the effect of the DHS inhibitor on HIV strains that are resistant to currently available HIV drugs, including protease inhibitors, nucleoside analogues and non-nucleoside reverse transcriptase inhibitors, as well as two strains resistant to all three drug classes. Despite these patterns of resistance, viral suppression was maintained at between 72 and 99%. They state, “the replication of HIV-1 isolates that are resistant to multiple antiretroviral drugs is sensitive to treatment with inhibitors of hypusine formation.”

Around seven days of treatment were required before HIV replication was fully suppressed. “These data suggest that the kinetics of CNI-1493 activity is rather slow, requiring approximately a full week until significant anti-HIV-1 effects can be observed,” conclude the investigators. Conversely, the drug’s activity was maintained for around seven days after it was removed from the cell cultures.

However, after checking for the development of resistance by treating cells with a low dose of CNI-1493 for twelve weeks, the researchers failed to observe the development of any resistance to the drug. This led them to conclude that "adaptation of viruses to CNI-1493 is rather unlikely."

No signs of non-specific toxic effects of CNI-1493 were observed, since cell death, activity and viability were unaffected by the drug. Furthermore, as the drug is currently in an international phase II trial for the treatment of Crohn’s disease, its safety has already been established. The doses being tested for Crohn's disease produce drug concentrations in the body that are higher than the effective anti-HIV level of 0.5 to 1.0µM.

“These data indicate that a therapeutic window exists for HIV chemotherapy using novel types of DHS inhibitors,” conclude the investigators. “Human DHS is a novel and valuable drug target that can be exploited for the development of advanced antiretroviral therapies.”