Treatment Issues: Newsletter of Experimental AIDS Therapies - Volume 13, Number 3, March 1999
Vicki Burkitt
Commercial preparations of human chorionic gonadotropin (HCG), a hormone secreted in abundant quantities during the first trimester of pregnancy, inhibit the growth of Kaposi's sarcoma (KS) in immunodeficient mice as well as in test tube cell cultures. HCG also attenuates human KS lesions when administered either locally or systemically. Recently, studies have shown antiviral effects in SIV-infected monkeys and transgenic mice containing certain HIV genes.
The source of these inhibitory effects has been controversial. The active molecule could be the beta subunit of HCG, which is a protein made up of alpha and beta subunits. Alternatively, the ameliorating effects might stem from one of the other proteins present in commercial HCG preparations. (These products are extracts from the urine of pregnant women.) A report analyzing the antiviral effect of two such enzymes has just been published (S. Lee-Huang et al., Proceedings of the National Academy of Sciences USA, March 1999, pages 2678-81).
The authors fractionated commercial HCG, separating out proteins and HCG subunits on the basis of charge and size. They then characterized the amino acid sequences of the collected fractions. The isolated proteins comprised the following: urinary beta-core HCG (a degradation product from the subunit), human RNase U, urinary lysozyme C. Human RNase A exists as part of the HCG beta-core and was difficult to purify.
When the authors screened these proteins for anti-HIV activity in cell lines chronically infected with HIV-1, there were a few surprises. beta-core HCG did not reduce production of the HIV core protein (p24), whereas the isolated lysozyme C and RNase U reduced p24 production by up to seven-fold in a concentration-dependent manner. Bovine pancreatic RNase A showed similar activity, as did lysozymes from human milk, human neutrophils and chicken egg whites.
RNases typically break up RNA (ribonucleic acid) in cells, whereas lysozymes attack the complex sugars (polysaccharides) in bacteria cell membranes. The authors tested whether the purified HCG-associated proteins performed in this fashion. When total cellular RNA from HIV-1 infected lymphocytes was incubated with individual protein fractions and the products run on an RNA separating gel, the human RNase U fraction, but not the HCG beta-core, degraded the RNA. Likewise, the isolated human lysozyme C lysed the bacteria Micrococcus lysodeikticus.
These anti-HIV proteins are comparable in molecular weight to active agents isolated from HCG preparations, but not further identified, in previous studies by the University of Maryland Institute of Human Virology led by Robert Gallo. (See Y. Lunardi-Iskandar et al., Nature Medicine, April 1998, pages 428-34). Since they occur naturally and are not toxic to cell cultures at the doses tested, they may be keys to new and safer strategies for treating HIV infection.
In an interview, Dr. Gallo noted that several research teams in the past year have tried to identify the active antiviral agents in HCG preparations. He said, for example, that the molecules identified by a research group from New York University "might have an anti-HIV effect, but they're not what we are looking for." The so-called HAF, or HCG-associated factor, that his lab previously isolated has now been identified, and a report on its characteristics will be written later this year. The natural function of that molecule seems related to early fetal development and the killing of superfluous cells.
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