Patofyziologie
The primary HSV-1 latency-associated transcript (LAT)
- Approximately 8.3-kb long noncoding RNA
- Is spliced to form stable 2.0 and 1.5 introns with lariat structures
- LAT has a neuron-specific enhancer that promotes its expression in the nucleus of latently infected cells
- Two LAT introns are expressed antisense to the HSV ICP0 immediate-early gene.
- Deleting the LAT from HSV reduces the frequency of reactivation
- Replacing the HSV-2 LAT with the HSV-1 LAT results in HSV-2 with a reactivation frequency similar to that of HSV-1
- LAT has also been implicated in protecting latently infected neurons from apoptosis
- In contributing to modification of histones to regulate expression of latent and lytic genes
- www.jci.org/articles/view/136225
Herpesvirus microRNAs (miRNAs)
- Expressed during latency
- Inhibit expression of lytic genes
- Regulate expression of host cell genes to evade recognition of latently infected cells by the host immune system
- Viruses must be able to reactivate from latency to infect other hosts
- Usually initiated by host cell signaling in response to external signals
- UV irradiation triggering the DNA damage response or allogeneic stimulation
- Internal signals
- Apoptosis, hypoxia, or metabolic stress
- Activate expression of immediate-early virus genes to initiate lytic replication
- www.jci.org/articles/view/136225
HSV infekce
- Upon infection of permissive cells, the HSV genome is assembled into chromatin structures
- That initially exhibit both H3K9me3 and H3K27me3 repressive histone methylation signatures
- Initiation of lytic infection requires recruitment of a
- Cellular transcriptional coactivator complex (HCF-1)
- That contains histone H3K9 demethylases (LSD1, JMJD2s)
- Histone H3K4 methyltransferases (SETD1A, MLLs)
- Limits the accumulation of H3K9me3
- Increases the levels of active H3K4me3
- To promote the transcription of viral immediate-early (IE) genes
- Levels of H3K27me3
- Associated with the viral genome decrease over the course of productive infection
- Dependent on IE protein ICP0 and viral DNA replication
- H3K9me3 and H3K27me3 markers
- Associated with the establishment and maintenance of HSV latency in sensory neurons
- Inhibition of either the HCF-1-associated H3K9 demethylases or the UTX/JMJD3 H3K27 demethylases
- Prevents productive viral reactivation
- journals.asm.org/doi/10.1128/mBio.01141-17
HSV inhibice IFNgamma
- Herpes Simplex Virus Type 1 Suppresses the Interferon Signaling Pathway by Inhibiting Phosphorylation of STATs and Janus Kinases during an Early Infection Stage
Psoriatic outbreaks with herpesvirus infection described
- Tamoxifen may have either diminished her circulating estrogen levels or blocked the hormone's action
- Thus tempering HSV recurrences
- When the drug was discontinued, the outbreaks returned with a worsening of her psoriasis.
- HSV v.s. plays a role in psoriasis exacerbation more often than we now realize.
- www.jaad.org/article/S0190-9622(02)70159-X/fulltext
- Associated VZV-viremia was present
- May have played a role in the triggering of the psoriasis
- Viral infections and interferon (IFN)-alpha
- Play a role in triggering dendritic cell populations in psoriasis
- INF-alpha and granulocyte monocyte colony stimulating factor (GM-CSF)
- Peripheral monocytes transform into INF-dendritic cells (DC’s)
- Similar to those involved in psoriasis pathogenesis
- INF-DC’s express a large range of toll-like receptors (TLR’s) including
- TLR 7 and 8
- Responsive to (viral) single stranded RNA (ssRNA)
- Incubation with ssRNA increased the IFN-DCs mRNAs for
- Interleukin (Il) IL-12p35, IL-12p40, IL-23p19, IL-27p28 and IL-27EBI
- Viral infections may potentially trigger psoriasis
- Resemblance exists between some VZV constituents and epidermal keratins to that observed for streptococci, remains to be determined.
- opendermatologyjournal.com/contents/volumes/V6/TODJ-6-9/TODJ-6-9.pdf
