Protein in St. John’s Wort may suppresses HIV-1 gene expression
Research suggests interesting possibilities
St. John’s Wort contains a protein that inhibits HIV-1 replication, according to new research.
Investigators who have spent more than a decade studying the mechanism of development of neurological disorders in AIDS patients decided to look at the impact St. John’s Wort might have on neuronal cells, says Kamel Khalili, PhD, director of the Center for Neurovirology, professor, and acting chair of the department of neuroscience at Temple University’s School of Medicine in Philadelphia, PA.
"We thought it was a good idea to see if there was any effect of the extract of St. John’s Wort on viral replication," Khalili explains. "Our initial investigation showed that crude extracts of St. John’s Wort inhibit HIV-1 gene expression in cells such as astrocytes in HIV-1 and in a number of other cells, including macrophages."
A protein from a callus culture of St. John’s Wort inhibits transcription of the HIV-1 long terminal repeat by affecting the activity of a transcription factor that regulates expression of the HIV-1 genome in macrophages and monocytic cells, C/EBP-beta, and the viral transactivator, Tat.1
The findings were unexpected, Khalili says.
After purifying the protein and sequencing it, investigators found that it was a novel protein, he says.
"So we decided to clone the gene for that protein, and it turned out that when it was expressed in the cells it affected HIV-1 replication," Khalili says. "It confirmed our first observation, and instead of using a crude extract, we’re using the product of a cloned gene."
Researchers used a water-soluble protein extract from culture callus tissue of the plant, which they obtained from the Institute of Botany in Armenia.1
"They had already set up the conditions for growth of this callus culture in the laboratory," Khalili says.
"The St. John’s Wort someone might find on the [retail] shelf may not actually effect the viral replication," Khalili adds. "We did an experiment with a commercially available St. John’s Wort preparation and examined its effect on HIV gene transcription in the lab, and that effect was so little, if any, that it wasn’t worth pursuing."
However, researchers theorize that the culture callus tissue grown in the laboratory environment overproduces the protein and enriches the extract.
The St. John’s Wort protein binds to C/EBP-beta protein, and its interaction keeps the protein in the cytoplasm, preventing it from entering into the nucleus, Khalili says.
"So when the protein is sequestered from the nucleus it doesn’t effect viral genic expression," Khalili says.
The inhibition of the St. John’s Wort protein is at the level of gene expression, which means that it may control the virus when it is in a latent stage, Khalili explains.
While there are similar approaches in the antiretroviral treatment pipeline, none have yet made it to market, Khalili says.
The next step is to further investigate the St. John’s Wort protein and identify a minimum region of protein that has the same beneficial effect, Khalili says.
"Then based on the feature of this protein, a small molecule that would inhibit function of C/EBP-beta and Tat could be developed," Khalili says. "We could use that molecule for blocking viral replication, and that’s obviously the long-term goal."
To achieve this first step, researchers will seek funding from the National Institutes of Health (NIH), Khalili notes.
"What I would suggest is this would make an additional compound in the cocktails that could be utilized for antiretroviral replication, and it could be a strong component of that cocktail," Khalili says.
"I have worked with HIV for over 20 years, and I have learned that in order to effectively block viral replication by targeting expression, you may need to target several different factors rather than a single factor," Khalili adds. "So I think this is a protein that can be utilized in conjunction with other compounds in the market or under development."
Reference
- Darbinian-Sarkissian N, et al. p27(SJ), A Novel Protein in St. John’s Wort, That Suppresses Expression of HIV-1 Genome. Gene Ther. 2005;[epub ahead of print].
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