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A new protein called KHNYN has been identified as a missing piece in a natural antiviral system that kills viruses by targeting a specific pattern in viral genomes, according to new discoveries published today in eLife.
The study of the body's natural defenses against viruses and how viruses evolve to escape is essential to the development of new vaccines, drugs and cancer treatments.
The genetic information that makes up the genomes of many viruses consists of building blocks called nucleotides of RNA. Recently, it was discovered that a protein called ZAP binds to a specific sequence of RNA nucleotides: a cytosine followed by a guanosine, or abbreviated CpG.
The human immunodeficiency virus (HIV) normally escapes ZAP inhibition as it has evolved to have little CpG in its genome. However, when CpGs are reintroduced into the virus, ZAP promotes its destruction. This helps us understand why HIV with more CpG does not multiply so well, and probably explains why many strains of HIV have evolved to have only CpGs. But one mystery remained because ZAP is unable to break down viral RNA by itself.
"Since ZAP can not degrade RNA by itself, we think that it has to recruit other viral RNA proteins to destroy it," said Lt./A. lead author Mattia Ficarelli, doctoral student at Chad's Swanson & s Department, Department of Infectious Diseases, King's College. London. "Thus, in this study, we sought to identify novel human proteins that are essential for ZAP to target viral RNAs to be destroyed."
After discovering that KHNYN was interacting with ZAP, the team tested what was going on when it increased the amount of KHNYN produced in typical HIV-infected cells with low levels of CpG or genetically engineered to have many CpGs. The increase in KHNYN production in cells reduced the typical HIV capacity to multiply by about five and decreased the ability of CpG-enriched HIV to multiply about 400-fold.
To determine if KHNYN and ZAP work together, the team repeated the same experiments in cells without ZAP and found that KHNYN did not inhibit the multiplication capacity of CpG-enriched HIV. They then examined what was happening in genetically engineered cells so as not to present KHNYN, and found that CpG-enriched HIV and a mouse leukemia virus containing many CpGs were no longer inhibited by the ZAP.
"We have identified that KHNYN is needed for the ZAP to prevent HIV from multiplying when it is enriched for CpGs," says co-corresponding author Professor Stuart Neil of the Department of Infectious Diseases of the King & # 39; s College of London. He adds that KHNYN is probably an enzyme that cuts the viral RNA to which ZAP binds.
"An interesting potential application of this work is to make new vaccines or treat cancer," added author and keynote speaker Chad Swanson, from the same department. "Since some cancer cells have low levels of ZAP, it may be possible to develop CpG-enriched anticancer viruses that would not harm healthy cells, but more research is needed to find out more. how ZAP and KHNYN recognize and destroy RNA before they can explore such applications. "
Source: eLife
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