Exploitation is a common theme in all fields of biology and viruses are no exception. But now it seems that viruses are up to some creative tricks when it comes to keeping a low profile in preparation for their full attack and sneaking out a few infections, a process known as viral latency. While DNA methylation may function as an ‘anti-virus’ system, sometimes epigenetic marks are just what a foreign virus needs. Despite not having epigenomes of their own, viruses have come up with a number of clever ways to exploit the epigenome of their host to weaken them and/or use it for their own evil doing.
Hijacking Host Chromatin Remodelling Complexes
In one of the most recent studies of virus–epigenome interaction researchers from the Wistar Institute in Philadelphia provide some key counter-intelligence on molecular pirates by giving away the details on virus induced chromatin remodelling via the hijacking (aka reprogramming) of the Daxx H3.3 chaperone. This unique instance of molecular hijacking for viral latency is performed by the Epstein-Barr virus (EBV). By using co-immunoprecipitation, size-exclusion chromatography, and fluorescence recovery after photobleaching the research team’s clever counter-intelligence operations revealed:
- The EBV tegument protein (BNRF1) binds the histone H3.3 chaperone Daxx.
- BNRF1 then goes onto hijack Daxx, where it influences histone H3.3 placement and chromatin accessibility.
- BNRF1 replaces that standard repressive cochaperone pilot (ATRX) and forms a unique complex: BNRF1-Daxx-H3.3-H4
- Adding some causation, mutations of BNRF1 in the predicted nucleotide binding site attenuates the chain of events that lead to the displacement of ATRX in the complex.
Ultimately, it appears that BNRF1 achieves a double whammy by preventing the establishment of antiviral repressive chromatin in the host, while also creating a chromatin profile on the EBV that enhances viral gene expression during the early stages of infection and is primed for the expression of latent viral genes.
Learn how to hijack chromatin remodellers in the Journal of Virology, December 2014.
DNA Methylation as a Viral Latency Cloak
The covert action doesn’t end at EBV since HIV infection also exploits the epigenome to achieve its viral latency, although its mechanism is through modifying DNA methylation. HIV is capable of remaining latent during the most brutal of anti-viral assaults which led to investigations into the mechanism behind this. Researchers were able to show that HIV uses two CpG islands that flank its transcription start site in order to recruit the hosts MBD2 and HDAC2 and use it to achieve its deadly silencing. The team was able to add the icing to their cake by coaxing the virus out of hiding by treatment with 5aza (which leads to a loss of methylation).
Histone Hijacking and Nucleosome Positioning
Herpes has also taken the spotlight for its hijacking of host histones by evolving sequences for nucleosome positioning. In a paper published in 2013 researchers demonstrated that throughout infection nucleosomes are associated with nuclear herpes DNA in a non-random and highly predictable fashion, suggesting they encode sequences for nucleosome positioning. This hijacked nucleosome organization is initially largely dependent on the viral DNA sequence, but in later stages a viral protein (IE1) appears to instruct the remodelling of the newly acquired viral chromatin for later stages of infection.
The take home message is that while herpes doesn’t carry its own histones when encapsidated, it is capable of manipulating the host chromatin environment through encoding its own nucleosome organization as well as having its own nucleosome reorganizing mechanisms.
Mimicking Epigenetic Machinery
Sometimes viruses don’t have to resort to theft, when fraud will do just as fine. The common flu has a protein that mimics the histone H3 tail. This decoy protein can act as substrate for a number of histone modifying enzymes, taking advantage of the fact that all these proteins really seem to care about is tail. Disrupting the usual Histone H3 function is nothing to sneeze at since histone H3 is involved in anti-viral response by binding TFs and forming a transcription complex related to antiviral expression.
The decoy protein binds the same TFs as Histone H3 and accumulates on promoters induced by viral infection and manages to stay on the mark and only affect viral response genes (and not housekeeping ones), allow the virus to avoid eradication by the hosts defences, without disrupting important cellular processes.
Human miRNA Embedded in Viral Protein Coding Genes
While the above show that viruses can hijack the epigenome in order to hide from the host, there are some cases where we aren’t quite sure what the viruses are up to. One such example is the discovery by Suraiya Rasheed and Rock Star Student Dexter Holland of human miRNA seed sequences embedded in the protein coding sequence of HIV genes. This gives the potential for naturally occurring viral coding transcripts to act similar to ‘standard’ non-coding RNA. Rasheed shares that “All microRNAs are supposed to be noncoding. Since we found the miRNA sequence to be a part of protein-coding sequence of the virus, these microRNA-like sequences are not acting in a canonical fashion. In general, genetic recombination (joining of two or more sequences) is very common in pathogenic organisms.”
Exploiting the Epigenetic Exploiters
These viral mechanisms aren’t all bad news as this knowledge can be used to trick the virus into some double espionage, like in the case of a prostate cancer treatment that uses miRNA switches placed in the Herpes virus. Researchers engineered the miRNA switches into to the herpes virus, which allows the virus to be active in cancerous cell, but then be shut off by miRNAs unique to healthy cells. By doing this the team was able to create a great search-and-destroy system that avoids the normal causalities of cancer treatments.
Infecting the Epigenetic Landscape
Ultimately, it appears that epigenetic exploits are common and important molecular mechanisms that viruses rely on. While they don’t have their own epigenomes, viruses are more than capable of taking over for their host at every level of the epigenetic landscape to achieve some of their most devastating features, particularly viral latency. It seems that in this case the best camouflage is the local molecular ‘fauna’. A deeper understanding of these hijacking mechanisms has a world of potential for the clinic.