A research team led by UCLA has identified a natural protein that can block a number of deadly viruses including HIV, Ebola, Rift Valley Fever, and Nipah. They published their findings in the current issue of the journal Immunity.
The protein, cholesterol-25-hydroxylase (CH25H), is an enzyme that converts cholesterol to an oxysterol called 25-hydroxycholesterol (25HC), which can permeate (pass inside) a cell’s wall and block a virus from getting entering. The CH25H enzyme is activated by interferon, which is an essential antiviral cell-signaling protein produced in the body, explained lead author Su-Yang Liu, a student in the department of microbiology, immunology, and molecular genetics at the David Geffen School of Medicine at UCLA. He conducted the study with principal investigator Genhong Cheng, a professor of microbiology, immunology and molecular genetics.
Liu explained, “Antiviral genes have been hard to apply for therapeutic purposes because it is difficult to express genes in cells. CH25H, however, produces a natural, soluble oxysterol that can be synthesized and administered. Also, our initial studies showing that 25HC can inhibit HIV growth in vivo should prompt further study into membrane-modifying cholesterols that inhibit viruses.” He explained that the discovery is particularly relevant to efforts to develop broad-spectrum antivirals against an increasing number of merging viral pathogens.
Liu and Chang worked with Jerome Zack, a professor of microbiology, immunology and molecular genetics and an associate director of the UCLA AIDS Institute. They initially found that 25HC dramatically inhibited HIV in cell cultures. Next, they administered 25HC to mice implanted with human tissues and found that it significantly reduced their HIV load within seven days. The 25HC also reversed the T-cell depletion caused by HIV. In contrast, mice that had the CH25H gene knocked out were more susceptible to a mouse gammaherpes virus. In collaboration with Dr. Benhur Lee, a professor of pathology and laboratory medicine and a member of the UCLA AIDS Institute, they discovered that 25HC inhibited HIV entry into the cell. Furthermore, in cell cultures, it was found to inhibit the growth of other deadly viruses, such as Ebola, Nipah and the Rift Valley Fever virus.
As previously noted, CH25H expression in cells requires interferon. The protein has been known for more than 60 years to be a critical part of the body’s natural defense mechanism against viruses; however, the protein itself does not have any antiviral properties. Rather, it triggers the expression of many antiviral genes. Liu explained that previous studies have identified some antiviral genes that are activated by interferon; however, this research gives the first description of an interferon-induced antiviral oxysterol through the activation of the enzyme CH25H. It provides a link to how interferon can cause inhibition of viral membrane fusion.
Liu noted some limitation of the study. For instance, 25HC is difficult to deliver in large doses, and its antiviral effect against Ebola, Nipah, and other highly pathogenic viruses have yet to be tested in vivo (a living subject). Also, the researchers still need to compare 25HC’s antiviral effect against other HIV antivirals.
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