Human herpes viruses, also known as HHVs, are part of a family of DNA viruses that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. The mechanism that controls this is very complex because expression of viral proteins during latency is decreased a great deal, meaning that the virus must have transcription of its genes repressed. There are many factors and mechanisms that control this process and epigenetics is one way this is accomplished. Epigenetics refers to persistent changes in expression patterns that are not caused by changes to the DNA sequence. This happens through mechanisms such as methylation and acetylation of histones, DNA methylation, and non-coding RNAs (ncRNA). Altering the acetylation of histones creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for transcription machinery to access the DNA. Methyl and acetyl groups can also act as binding sites for transcription factors and enzymes that further modify histones or alter the DNA itself.
Herpes virus life cycle
Human herpesviruses are all double stranded DNA viruses that enter the nucleus of the host cell. HHVs replicate in the nucleus of the infected cells and can enter both a lytic and latent phase. In the lytic phase, the viral genes are being actively transcribed and many times ultimately lead to cell death. In the lytic phase the virus is able to spread to other hosts due to open sores and other such mechanisms. In the latent phase the amount of viral transcript is heavily reduced. In this phase the host will show little to no signs of virus infection. This state can be maintained for very long periods of time and infection with HHVs can last a lifetime.
Herpes simplex virus 1 and 2
Herpes simplex virus 1 and 2 (HSV 1 and HSV 2) are part of the alpha subfamily of HHVs. The lytic phase of infection occurs within mucoepithelial cells while the latent infection of these cells occurs in neurons. These two viruses are the cause of oral and genital herpes.
Latency is maintained in a variety of ways, one of which is the latency-associated transcript, or LAT. This long non-coding RNA accumulates in the latent phase and has been found to suppress the lytic genes. It is also possible that the LAT transcript plays a role in determining which neurons become infected and maintain the lytic phase. LAT manages this suppression of the viral genome through miRNAs that block viral transcription factors such as ICP0 and ICP4 that play a very important role in the lytic phase of infection. Another mechanism that is used to maintain the latent phase is chromatin remodeling. During the latent phase, researchers have found more methylated chromatin in the lytic genes and less acetylated chromatin, whereas in the LAT region there is less methylation and more acetylation found during latency. This was reversed during the lytic phase, Suggesting that this change of chromatin structure is used to control the and maintain the lytic and latent phases.
Varicella zoster virus
Varicella zoster virus (VZV) is a member of the alpha subfamily of herpesviruses and is responsible for the human diseases of the chicken pox and shingles. These viruses have their lytic phase in mucoepithelial cells and are latent in neuronal cells.
Unlike HSV 1 and 2, there has not been any LAT found in the VZV latent cells. Instead, it appears that the main way that expression of viral transcripts is maintained at a lower level during latency is through chromatin structure. There are 5 transcripts identified during latent infection of VZV. Open reading frames (ORFs) 21, 29, 62, 63, and 66 are all expressed with 62 and 63 being the most abundant. The promoters of these two genes, ORFs 62 and 63, contain large amounts of acetylated H3K9, which makes these genes euchromatic. This contrasts other genes normally found in lytic infection that are not associated with acetylated H3K9 histones during latency. This means that these genes are controlled through a mechanism affecting the chromatin structure that allows them to be expressed in the latent phase. The mechanism of how this happens is not clearly understood and research is currently being done in this area.
