Microscopy image of HIV-1 (in green) emerging from an infected human cell. Image credit: Public Domain
Like many viruses, the genetic information of the human immunodeficiency virus (or HIV for short) is formed of molecules of RNA, which are sequences of building blocks called nucleotides. Once the virus is inside human cells, a protein called ZAP can identify viral RNAs by binding to a precise motif, a combination of two nucleotides called CpG. This allows the cell to destroy the viral RNA, thus preventing the virus from multiplying. However, HIV and other viruses that infect mammals are often able to ‘hide’ from ZAP because their genetic codes have many fewer CpG nucleotides than what would be expected by chance.
ZAP by itself does not appear to be able to cut up RNA, so it is thought that it recruits other, as yet unidentified, proteins to destroy the genome of viruses. Here, Ficarelli et al. used genetic techniques to identify a new human protein called KHNYN that interacts with ZAP.
First, a new version of the RNA genome of HIV was engineered, which contained higher numbers of CpGs: this CpG-enriched virus could be inhibited by ZAP in human cells. The experiments showed that increasing the amount of KHNYN protein led to lower levels of HIV genomes enriched in CpG. However, increasing the levels of KHNYN protein in mutant cells without ZAP had no effect on how well CpG-enriched HIV multiplied. CpG-enriched HIV and another related virus with many CpG nucleotides were able to multiply more successfully in mutant cells lacking the KHNYN protein than in normal cells. Further experiments also suggested that mutating a region of KHNYN which is likely to cut RNA prevented it from inhibiting HIV enriched with CpGs.
Artificially manipulating the CpG nucleotide content of viral sequences could help create viruses useful for human health. For instance, weakened viruses could be designed for use in vaccines. Some human tumors have decreased levels of ZAP, and it could therefore be possible to build viruses that healthy cells can destroy, but which could multiply in and kill cancer cells. However, before these approaches can be developed, exactly how ZAP and KHNYN degrade strands of viral RNA needs to be characterized.
