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Published in the Bulletin of Experimental Treatments for AIDS July 1998 issue, by the San Francisco AIDS Foundation. |
DRUG WATCH: Human Chorionic Gonadotropin - Associated FactorBy Liz Highleyman Recent research has shown that a factor associated with human chorionic gonadotropin (hCG) may be a potential therapy for Kaposi's sarcoma (KS), HIV disease, cancer and anemia. The newly discovered factor -- which has been named human chorionic gonadotropin-associated factor, or HAF -- was isolated by Robert Gallo and colleagues at the Institute of Human Virology at the University of Maryland in Baltimore. A report of their findings appears in the April 1998 issue of Nature Medicine. Earlier studies of hCG had produced mixed results, with some showing that hCG caused KS tumors to shrink and HIV blood levels to decline, and others showing no effect. The new research indicates that a factor associated with hCG -- rather than hCG itself -- is responsible for the beneficial effects. Human chorionic gonadotropin is a hormone produced by the placenta supporting the fetus, and is found in the urine of women during early pregnancy. It helps maintain the correct environment to allow the fetus to develop. HCG is made up of 2 pieces, or subunits, called alpha and beta chains. KS is an opportunistic cancer that affects many people with AIDS, in particular gay men. KS is characterized by purplish lesions on the skin and may also affect internal organs. Scientists have recently determined that the condition is caused by a sexually transmitted virus called Kaposi's sarcoma-associated herpesvirus, or KSHV (also known as HHV-8). Early HCG DiscoveriesHCG was found to have anti-KS effects due to a mishap in the Gallo tmor biology laboratory in 1995. Male and female mice that had been injected with KS cells were accidentally put together in the same cage. Nature took its course, and researchers noticed that the female mice that became pregnant did not develop KS, while the male mice did. In addition, it had been reported some years previously that a small number of HIV positive women experienced a remission of KS when they became pregnant, then relapsed after they gave birth. Gallo and his colleagues concluded that some factor associated with pregnancy was responsible for the results, and they began studying chorionic gonadotropin. When the researchers tried using crude preparations of hCG in HIV-infected people with KS, they found that hCG preparations decreased the size of KS tumors and reduced the amount of HIV in the blood of some patients. HCG preparations also reduced viral load, increased CD4 T-cell counts and led to weight gain in monkeys infected with simian immunodeficiency virus (SIV). Uncovering the Mystery FactorIn the studies reported in April, the University of Maryland group found that purified or recombinant hCG and preparations containing only alpha or beta chains of hCG did not have the expected anti-KS and antiviral effects. This led the researchers to believe that some other factor in crude hCG preparations -- rather than hCG itself -- was responsible for the beneficial effects. The existence of such a factor had previously been suspected by other scientists. Gallo and his colleagues used a technique called gel permeation chromotography to separate clinical grade hCG preparations and concentrates of urine derived from pregnant women into various components on the basis of molecular weight. When the researchers filtered out the hCG and isolated the remaining components, they found 2 substances -- which they call HAF -- that had an anti-tumor effect when injected into mice and stimulated the growth of blood cells in laboratory culture tests. Although the identity of HAF is not known, researchers believe that it is a protein that attaches to hCG. According to Gallo, "I think we are getting close to identifying what the material actually is. It's a small protein, and it's completely separable from hCG." The researchers showed that HAF interferes with HIV replication in CD4 T-cells and macrophages in laboratory culture tests by inhibiting the activity of HIV genes. In addition, HAF also stimulates the production of red and white blood cells in the bone marrow. At the same time, the factor suppresses the growth of new blood vessels (angiogenesis); it is this effect which reduces the size of KS lesions, and it may be helpful in controlling other types of cancer as well. So far, the factor does not appear to have toxic side effects, although this cannot be known for sure until further studies are conducted. The discovery of HAF explains why hCG appeared effective against KS in some but not all earlier studies: some of the hCG preparations used in studies contained HAF, while other more purified preparations lacked the factor. HAF is present, although probably at low concentrations, in some commercial clinical grade hCG preparations. These preparations are used to treat undescended testicles and underproduction of testosterone in boys. The Future of HAFNow that the existence of HAF is known, researchers will attempt to determine the factor's chemical identity and structure, and to produce a purified version for medical use. A purified HAF produced by recombinant technology could allow the factor to be produced in large amounts and used in higher concentrations. Currently the factor is only available from the urine of women in the first trimester of pregnancy. Gallo estimates that HAF will probably not be available as a drug for human use for at least 2 years. Liz Highleyman is Assistant Editor of BETA.
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