Suppression of CG dinucleotides in viruses may help them to evade our cellular defences

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Humans and viruses have long engaged in a constant tug-of-war– as our cells evolve new ways to defend us from these pathogens, our viral enemies in turn also acquire new traits to circumvent our defences.

In a recently published study from Nature, a team of researchers have found that for HIV and other viruses, specific variants in the genetic code are critical for viral replication and infection. Through synonymous mutagenesis, they discovered that CG suppression is essential for HIV-1 replication.

The lack of CG dinucleotides observed is not an unusual trait, as humans also lack this dinucleotide sequence but for alternative reasons. “Because of this evolutionary loss, the human genome now has about 80% fewer CG sequences than we would expect by chance,” explained Matthew Takata (The Rockefeller University, NY, USA), who was the lead author of the study.

“Many viral genomes cannot go through the same chemical modification process that vertebrate genomes like our own have experienced,” added Paul Bieniasz (The Rockefeller University), co-author of the study. “This led us to ask: how and why did HIV and other viruses lose their CG sequences?”

The researchers hypothesized that a cellular surveillance system might exist to identify and destroy CG sequences, thereby preventing viral infection. They exploited a siRNA screening technique in order to search for proteins in the cell that might serve as such a defence mechanism. In human cells, they found that ZAP (an antiviral protein) was able to recognize molecules that contain many CG sequences. ZAP binds to the sequences, identifies them as foreign and then destroys these viral genomes.

Additionally, using CRISPR–Cas9 technology, the researchers mutated cells in order to knockout ZAP and discovered that this enabled viral replication to occur. They then used CLIP to identify the binding site of ZAP on HIV and revealed that this was the CG region itself.

Their results offer insight into what caused HIV and other viruses to lose their CG sequences over time. It’s very likely that these viruses have adapted to evade mammalian defence mechanisms, evolving to remove their CG sequences and thus, avoid surveillance by ZAP. In their study, researchers speculate, “it appears that the main targets of ZAP are non-self, viral RNAs in which CG suppression in incomplete.”

Although HIV and many other viruses contain few CG dinucleotides like ourselves and thus, do not get destroyed by ZAP, the researchers believe that this protein still serves to protect us against other pathogens. “Its activity may provide defence against viruses from other species, such as biting insects, whose genomes still have high numbers of CG sequences,” commented Bieniasz.

One potential application of their research may be in the development of attenuated viruses to make vaccines. By genetically engineering a virus to contain an increased number of CG dinucleotides, vaccines could prompt people’s immune systems to produce immunity against the pathogen.

“Recoding a virus with many additional CG sequences is likely to be an effective, adjustable and largely irreversible way of attenuating it, making vaccine development faster and safer,” Takata concluded.

Sources: Takata MA, Gonҫalves-Carneiro D, Zang TM et al. CG dinucleotide suppression enables antiviral defence targeting non-self RNA. Nature 550, 124–127 (2017); www.eurekalert.org/pub_releases/2017-11/ru-itf111317.php  

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