Researchers in the US have identified a natural antiviral protein that stops HIV and certain other deadly viruses like Ebola, Rift Valley Fever, and Nipah, from entering host cells. They hope the discovery will help efforts to develop broad-spectrum antivirals against many of the deadly viruses that the National Institute of Allergy and Infectious Disease lists as “priority pathogens” for national biosecurity purposes.
The team, led by principal investigator Genhong Cheng, a professor of microbiology, immunology and molecular genetics at the University of California – Los Angeles (UCLA), writes about the discovery in the January issue of the journal Immunity.
The protein, called cholesterol-25-hydroxylase (CH25H), is an enzyme that converts cholesterol in the cell to an oxysterol called 25-hydroxycholesterol (25HC), which permeates the cell wall and blocks the virus from getting in.
The enzyme itself is triggered by interferon, an essential antiviral cell-signaling protein made in the body.
Cholesterol is present in every cell of the body. It is particularly abundant in the cell membrane, and helps to preserve its integrity.
Other approaches to preventing viruses from getting inside host cells have tried to do this by changing genes, but it is not easy to express genes in cells, says lead author Su-Yang Liu, a student in the department of microbiology, immunology and molecular genetics at UCLA’s David Geffen School of Medicine.
The advantage of CH25H is that it “produces a natural, soluble oxysterol that can be synthesized and administered,” says Liu.
In their study, using cell cultures, Liu and colleagues showed that 25HC broadly inhibited the proliferation of enveloped viruses like HIV, Ebola, Rift Valley Fever, and Nipah.
“It suppressed viral growth by blocking membrane fusion between virus and cell,” write the authors.
Membrane fusion is the way enveloped viruses gain entry into host cells: the envelope or “skin” of the virus fuses with that of the cell, after glycoproteins on the surface of the envelope identify and bind to receptor sites on the host’s membrane.
The researchers also tested the effect on HIV in live mice.
They gave 25HC to mice implanted with human tissue and found it significantly reduced their HIV load within 7 days.
The 25HC also reversed the depletion of immune system T-cells caused by HIV.
The researchers were intrigued to find that CH25H expression in cells requires interferon, a compound that we have known to be an essential component of the body’s natural defence against viruses for over six decades.
However, interferon itself does not have antiviral properties: it works by switching on antiviral genes. Previous studies have identified some of the genes that interferon activates, but this is the first study to describe it acting as a trigger for the production of antiviral oxysterol through the activation of the enzyme CH25H.
Liu says the findings give some clues about how interferon can block viral membrane fusion.
However, there is still a lot to do before the findings can translate to something useful in the clinic.
He points out that the study only tested 25HC’s antiviral effect on Ebola, Nipah and other highly pathogenic viruses, in cell culture. Tests against those viruses in live animals are still to be done. Another hurdle to overcome is that 25HC is difficult to give in large doses, and its performance compared with other HIV antivirals is also unknown.
Funds from the National Institutes of Health, the Warsaw Fellowship, the UCLA Center for AIDS Research, the UCLA AIDS Institute, the UCLA Clinical and Translational Science Institute, and the Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases helped finance the study.
Scientists at Stanford University School of Medicine recently reported a study where they genetically engineered HIV-resistant cells. If the method is effective in humans, it could give HIV-positive patients an alternative to the lifelong “cocktail of drugs” medication schedule that they currently follow.
Written by Catharine Paddock PhD