New Kind of HIV Antiviral: Food Spice, Cancer Drug Show Activity

Researchers at Harvard Medical School, using laboratory tests, have developed a new class of anti-HIV compounds -- substances which inhibit the LTR (long terminal repeat) sequence of HIV. Three substances which might have potential were reported in the March 1993 Proceedings of the National Academy of Sciences, USA. One, curcumin, is the main active ingredient in turmeric, a spice used in curry and other foods; another, topotecan, is being tested in humans as a possible cancer treatment; the third, beta-lapachone, has not been tested in humans, but laboratory and animal data suggest that it might be possible to find a useful dose.

HIV is often inactive, even after it has entered a cell and has become integrated in that cell's genetic machinery. (This does not contradict the recent report that HIV is active even early in the disease while there are no symptoms; the virus is active in some cells but not in others. For background information, see "AIDS Pathogenesis" in AIDS TREATMENT NEWS #172, April 2, 1993.) The LTR of HIV appears to be critically important in "turning on" the virus (causing it to produce the proteins which are assembled into new viruses, and which cause other harmful effects). The LTR also maintains viral activity after it has started, suggesting that inhibiting the LTR could slow or stop virus which has already been activated. Normally, many substances in the cells seem to be affecting the LTR -- either to inhibit it and keep the virus inactive, or to activate the LTR and promote HIV growth and activity. Much is unknown about how this process works and what substances may affect it. But a drug which effectively inhibited the LTR might keep the virus inactive indefinitely -- not only in acutely infected cells, but also in chronically infected cells, where AZT, ddI, etc. are largely ineffective.

Certain experimental treatments already in use in the community -- pentoxifylline, NAC, and antioxidant nutrients such as beta carotene, vitamin C or vitamin E -- may already be having some inhibitory effect on the HIV LTR. The Harvard work is new in that it demonstrates a way to systematically search for potential drugs which work through this particular viral target.

The Laboratory Experiments
The recent report described two kinds of experiments. One did not use any HIV or other virus; instead it used a genetically engineered human cell, which included a copy of the HIV LTR and also a "reporter" gene, controlled by that LTR, which creates an enzyme which could easily be detected in the laboratory. Scientists can grow this cell, and then add certain chemicals known to activate the LTR, and verify that the enzyme was indeed produced, as expected. Then they can add potential drugs, in various concentrations; if one of the drugs stops the enzyme from being produced, that drug is probably inhibiting the LTR. [Incidentally, the cells for this experiment were developed in the laboratory of Leonard Herzenberg, Ph.D., a Stanford researcher studying NAC, whose group uses the cells in their studies of HIV activation and repression.]

The other experiments used cells infected with HIV, to verify that the substances which showed anti-LTR activity did indeed show anti-HIV activity in the laboratory. Both acutely infected and chronically infected cells were used.

Results
The most powerful of the three substances found may be topotecan, which was active against HIV in very small concentrations, and is reasonably well tolerated in cancer patients, according to published research. These patients tolerated 200 times the blood level of topotecan required to reduce p24 antigen production (a measure of HIV activity) by 80 percent in chronically infected cells.

Curcumin, found in the spice turmeric, was less active than topotecan. But it may be particularly important because, as one of the study's authors, Bruce J. Dezube, M.D., points out, "it is a food additive, readily available, non-toxic, and a potential benefit for developing countries." The paper notes that curcumin has been eaten for thousands of years [it is used especially in India, where turmeric is a major ingredient of curry]. It has also been tested for potential pharmaceutical uses, and it has been used for various purposes in traditional Indian, Chinese, and Western herbal medicine.

The third substance, beta-lapachone, had no human toxicity data available, but is well tolerated in mice. It was tested 20 years ago for other purposes, and abandoned. Its patent has now expired, so it may be hard to find a pharmaceutical company to develop it.

The research which found these three potential treatments is also important because it demonstrated a method which could be used to screen thousands of potential drugs to look for LTR inhibitors. Because of limited resources, this project did not screen many candidates; instead, the researchers were selective, trying to pick substances they considered likely to work. About fifteen potential compounds were tested to find the three listed above.

The Next Step
The next step in the development of this approach is unclear, because these three potential treatments have reached the point at which new AIDS drugs usually stop. Potential treatments developed in laboratories by well-respected scientists usually do get into scientific journals, but in most cases nothing further happens, because usually there is no drug company which has or can acquire the rights, and also has an interest in the drug, and the money and other resources available to develop it. (The government does little drug-development work, and most of that is on drugs which companies are already testing.) Even those drugs which are ultimately successful often float around at this stage for several years, with progress largely stopped, before enough momentum develops to take them further. Of the three LTR inhibitors described above, two may be unpatentable, and the third is being developed by a company which, as far as we know, is not testing drugs for AIDS. We cannot rely on business as usual to get these substances tested.

The problem is that there is still no institution to examine potential treatments which have reached this stage, select which ones are promising enough to begin human testing, and then quickly get that testing to happen. When an "AIDS czar" is appointed, that office may be a place to go to get this long-standing omission addressed. But this official will have a small staff and will probably focus mainly on non-technical issues; in addition, it will be hard to start anything new because of budget constraints.

Community-based research groups might be able to help. Topotecan has already been tested in people as a cancer treatment, so basic dosage and safety information is known. Various permissions would be required to test it for HIV; these permissions might or might not be an obstacle. The company developing topotecan, SmithKline Beecham, is testing it for cancer but not for AIDS.

Curcumin, at least in turmeric, would certainly be accessible. However, one German paper reported that it was poorly absorbed when given orally to animals, and more active when given by intraperitoneal injection. But a study in India found protection against cancer-causing chemicals in cigarette smoke when turmeric was given orally to people. (Most of the traditional uses have been topical; one study in India, for example, reported a 97 percent cure rate for scabies with a preparation of turmeric mixed with another herb.) A community-based research organization could relatively easily review the available literature, review traditional medicinal uses, and test turmeric or curcumin in a few patients to see if it reduced viral activity. The inexpensive, commercially available acid-dissociated p24 antigen test could be used to look for an antiviral effect. Or it might be possible to use more sophisticated virological tests, through collaboration with the researchers who are developing them. If little or no effect is found, then it might be worth investigating whether curcumin could be prepared in an injectable form.

In past years, the only way the AIDS community could move a drug forward in the face of institutional neglect was to develop it as an "alternative" treatment -- i.e., let it go into widespread use -- in the hope that if there were any substantial value it would be noticed, and if not, the substance would be retired through the usual "drug of the month" process. Maybe we can do better today.

References
Li CJ, Zhang LJ, Dezube BJ, Crumpacker CS, and Pardee AB. Three inhibitors of type 1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA. March 1993; volume 90, pages 1839-1842.