HHV Latency Associated Transcript

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Infection by any of the Herpes Viruses (HHV) may lead to chronic viral infection which involves a dormant period known as latency. For example, the HHV-3 virus which causes Chicken Pox may also result in Shingles following many years of latency.

Latency Associated Transcript (LAT) is an RNA transcript of HHV DNA. During latency, most of the Herpes genome is silent, with the exception of the region which encodes LAT and LAT accumulates within infected cells.

After splicing, LAT is a 2.0-kilobase transcript (or intron) produced from an 8.3-kb region of DNA known as the Latency Associated Transcript Region or LAT-DNA.

Interactions with host cell biology

Production of Micro-RNA interfering with host cell genome, preventing apoptosis

Researchers at the University of Pennsylvania School of Medicine have determined that a portion of LAT consists of an interfering micro RNA (miRNA). This miRNA was termed miR-LAT, and shown to downregulate Transforming Growth Factor-β1 (TGFβ1) and SMAD3. These effects block apoptosis, or normal programmed cell death.

In research done at the Department of Veterinary and Biomedical Sciences, University of Nebraska Lincoln, G Henderson, Peng W, Jin L, and colleagues showed that the products from the first 4,658 nucleotides of LAT inhibited caspase- 8 and caspase-9 cellular death factors.

Human CTCF protein may regulate LAT expression

CCCTC-binding factor (CTCF) is a zinc finger protein which occurs naturally in some human cells. CTCF is localized to the nucleus of cells. CTCF has been shown to naturally regulate the expression of human linear dsDNA by binding with different target DNA sequences and proteins. This DNA binding may result in formation of transcription-ready euchromatin through the acetylating activity of CTCF.

In sequence analysis and quantitative genomics assays on HHV DNA, a study has shown that viral DNA and specifically the LAT region may be acetylated and deacetylated by human CTCF. These effects respectively promote and repress transcription of DNA to RNA.

Interactions with virus biology via proteomic and

Repression of viral lytic-gene expression

LAT results in changes to histone H3 production which convert the viral DNA into a non-productive form known as heterochromatin. ([link])

Farrell and colleagues report that the 2.0-kb intron terminates at the 5' end with a 750-base antisense RNA complement for HHV Infected Cell Polypeptide 0 (ICP0) gene. [link]

Downregulation of lytic gene (i.e., proliferative) products

QY Wang and colleagues reported, using assays comparing LAT-negative vs. LAT-positive virus strains, that LAT activity increases the amount of heterochromatin and decreases active chromatin on lytic-gene promoters. They showed that HSV lytic-gene promoters became methylated via epigenetic LAT activity. LAT may cause this effect through application of the human protein histone methyltransferase. [link]

Miscellaneous reports

• In five autopsied human cranial nerves, only 10% of infected neurons found to be positive for HSV-1 DNA were positive for HSV-1 LAT via in situ hybridization testing. K. Wang and colleagues reported on a comparison of laser-capture microdissection + real-time PCR for the HSV-1 gG sequence and the in situ hybridization test for HSV-1 LAT. Their specimens were 970 human trigeminal ganglia nerves from 5 subjects at autopsy. [link]

Footnotes