In a new study published in eLife, a new protein called KHNYN has been discovered as a missing piece in a natural antiviral system that kills viruses by targeting specific pattern in viral genomes. Studying the natural defenses of the body and how viruses evolve to evade them is vital to developing new vaccines, drugs, and anticancer treatments.
The genetic information that makes up the genomes for many viruses is comprised of building blocks called RNA nucleotides. In recent time, it was discovered that a protein called ZAP binds to a specific sequence of RNA nucleotides: a cytosine followed by guanosine or CpG for short.
Normally, the human immunodeficiency virus (HIV) escapes being inhibited by ZAP because it has evolved to have few CpGs in its genome. When CpGs are added back to the virus, however, ZAP promotes its destruction. This helps scientists understand why HIV with more CpGs multiplies less successfully and likely explains why many strains of HIV have evolved to have few CpGs. But a mystery remained because ZaP is unable to break down the viral RNA by itself.
Mattia Ficarelli, a Ph.D., a student in Chad Swanson's Lab, Department of Infectious Diseases, King's College London, the lead author of the study, said that as ZAP can't degrade RNA on its own, they believed that it must recruit other proteins to the viral RNA to destroy it. So, in the current study, they set out to identify new human proteins that are essential for ZAP to target viral RNAs for destruction.
After the researchers discovered that KHNYN interacts with ZAP, they tested what happens when they increased the amount of KHNYN produced in cells infected with a typical HIV that has few CpGs, or an HIV genetically engineered to have many CpGs. Increasing KHNYN production in the cells reduced the typical HIV's ability to multiply about five-fold and decreased the ability of the CpG-enriched HIV to multiply by about 400-fold.
The researchers attempted to figure out if KHNYN and ZAP work together by repeating the same experiments in cells without ZAP and discovered that KHNYN did not inhibit the ability of CpG-enriched HIV to multiply. Then, they looked at what happened in cells genetically engineered to lack KHNYN and found that ZAP no longer inhibits both CpG-enriched HIV and a mouse leukemia virus that has many CpGs.
Professor Stuart Neil, the co-corresponding author of the study from the Department of Infectious Diseases, King's College London, explained that they have identified that KHNYN is required for ZAP to prevent HIV from multiplying when it is enriched for CpGs. Neil added that KHNYN is possibly an enzyme that cuts up the viral RNA to which ZAP binds.
