HHV Latency Associated Transcript

Latency Associated Transcript or LAT is an RNA transcript of a subset of the Human Herpes Virus (HHV) dsDNA genome. LAT accumulates within infected cells during the latent period of HHV infection.

The mechanisms of latent infection by HHV are not known, but LAT is believed to be involved.

HHV LAT is a 2.0-kilobase transcript produced from an 8.3-kb transcription unit.

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

• Herpes simplex virus latency-associated transcript is a stable intron M Farrell, A Dobson, L Feldman, Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA, Proceedings of the Natural Acadaemy of Sciences, USA, Vol 88, pp.790-794, Feb 1991

LAT interacts with host proteins

HHV LAT may disrupt apoptosis (programmed cell death) protein factors.

Apoptosis is 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.

• Regulation of caspase 8- and caspase 9-induced apoptosis by the herpes simplex virus type 1 latency-associated transcript. Journal of Neurovirology, Dec 2002;Vol 8 Suppl 2, pp 103-111.

Human CTCF protein may serve a regulatory function on HHV dsDNA, especially LAT

CTCF binds to DNA and regulates its expression through acetylation/deacetylation.

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 [1] 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.

CTCF also binds to, acetylates, deacetylates, and regulates the LAT region of HHV DNA genome.

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.

• A Chromatin Insulator-Like Element in the Herpes Simplex Virus Type 1 Latency-Associated Transcript Region Binds CCCTC-Binding Factor and Displays Enhancer-Blocking and Silencing Activities. Amelio, McAnany, Bloom; University of Florida College of Medicine, Gainesville, FL; Journal of Virology, Mar 2006;80(5):2358-2368

LAT interacts with other parts of the HHV genome and has epigenetic effect.

HHV virus LAT may down-regulate production of lytic gene products which otherwise lead to production of virus.

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.

• Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection. Wang QY, Zhou C, Johnson KE, Colgrove RC, Coen DM, Knipe DM.; Department of Microbiology and Molecular Genetics, Harvard Medical School; Proceedings of the National Academy of the Sciences, USA, 1 Nov 2005, Vol 102, No 44, pp. 16055-16059, 24 Oct 2005

LAT may cause this effect through application of the human protein histone methyltransferase.

Miscellaneous reports about LAT

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.

• Laser-capture microdissection: refining estimates of the quantity and distribution of latent herpes simplex virus 1 and varicella-zoster virus DNA in human trigeminal Ganglia at the single-cell level. Wang K, Lau TY, Morales M, Mont EK, Straus SE.; Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA. kwang@niaid.nih.gov