Aug. 7, 2000 The results of a study led by a University of Iowa researcher suggest that a drug already undergoing stage I and II clinical trials as a cancer treatment may also have potential as an anti-HIV therapy.
The study, led by David Price, Ph.D., a UI professor of biochemistry working with Matija Peterlin at the University of California San Francisco and Adrian Senderowicz at the National Cancer Institute, found that very low concentrations of flavopiridol, a drug manufactured by Aventis Inc., blocks HIV-1 replication in cell culture experiments. These findings appeared in the July 21 online issue of the Journal of Biological Chemistry.
Flavopiridol strongly hinders the cellular process known as transcription, a multi-step process which results in the production of ribonucleic acid (RNA). Cells use the genetic information encoded by these long RNA molecules to make proteins.
Flavopiridol effectively blocks the action of an enzyme called P-TEFb, which controls one of the steps in the transcription process. In fact, flavopiridol is the most powerful P-TEFb inhibitor to date. In Price's test tube experiments, even extremely low concentrations of flavopiridol were effective at blocking the action of P-TEFb.
P-TEFb is required for transcription of the HIV-1 genome to occur. Flavopiridol inhibits P-TEFb, causing inhibition of transcription. In tests to investigate its effect on HIV-1 infection and viral spread in cultured human cells, Price's team found that the same low concentrations of flavopiridol that inhibited P-TEFb dramatically blocked HIV-1 infection and replication.
"Since P-TEFb is a key factor in HIV-1 infection and flavopiridol blocks HIV-1 propagation in culture, we believe that this substance should be tested as a potential anti-AIDS drug," Price said.
During infection, HIV-1 undergoes mutations in its DNA that allow its proteins to change and become resistant to drugs. This is one of the biggest problems with treatment of HIV. Many people are infected with HIV strains that are resistant to all known drugs. However, because P-TEFb is made by human cells and not by the virus, it cannot be changed during HIV infection, so strains resistant to flavopiridol should not arise.
Because it targets a key process in most cells, one concern about the therapeutic use of flavopiridol is that it could be toxic to humans. Although the current anti-cancer clinical studies with flavopiridol suggest that humans may be able to tolerate the drug, the maximal tolerated dose in cancer patients causes diarrhea and pro-inflammatory syndrome. The concentrations of flavopiridol required to achieve the anti-HIV effect seen in this study are much lower than those being used in the anti-cancer clinical trials. This might mean that side effects would be less of a concern if this drug were used as an anti-HIV treatment. However, Price cautioned that these results were only the beginning of the research process that might one day result in clinical trials.
Interestingly, HIV-1 seems to be particularly sensitive to the effects of flavopiridol on P-TEFb activity compared to the drug's effect on transcription of other cellular genes. One of the most important findings of this research is that flavopiridol does not appear to act against P-TEFb in the same way as other inhibitors of this enzyme. Indeed, it does not even seem to act the same way against P-TEFb as it does against other members of this enzyme family. P-TEFb is completely inhibited by concentrations of flavopiridol that do not affect other enzymes in the same family. This difference may be extremely important in terms of toxicity.
"The fact that HIV-1 virus should be so dependent on the activity of this particular enzyme may prove to be its Achilles heel," Price said. "Understanding how and why HIV-1 is so sensitive to P-TEFb inhibitors will be the focus of future work in my lab."
The research was supported by funding from the National Institutes of Health (NIH) and the Howard Hughes Medical Institute (HHMI).
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