HHV Latency Associated Transcript

HHV Latency Associated Transcript (HHV LAT) is a length of RNA which accumulates in cells hosting long-term, or "latent", Human Herpes Virus (HHV) infections. The LAT RNA is produced by genetic transcription from a certain region of the viral DNA. LAT regulates the viral genome and interferes with the normal activities of the infected host cell.

Herpes virus may establish life-long infection during which a "reservoir" virus population survives in host nerve cells for long periods of time. Such long-term Herpes infection requires a mode of cellular infection known as "latent" infection. During the latent infection, the metabolism of the host cell is disrupted. While the infected cell would ordinarily undergo an organized death or be removed by the immune system, the consequences of LAT production interfere with these normal processes.

Latency is distinguished from "lytic" infection; in lytic infection many Herpes virus particles are produced and then burst or "lyse" the host cell. Lytic infection is sometimes known as "productive" infection. Latent cells harbor the virus for long time periods, then occasionally convert to productive infection which may lead to a "recurrence" of symptomatic Herpes symptoms.

During latency, most of the Herpes DNA is inactive, with the exception of LAT, which accumulates within infected cells. The region of HHV DNA which enodes LAT is known as LAT-DNA. After splicing, LAT is a 2.0-kilobase transcript (or intron) produced from the 8.3-kb LAT-DNA. The DNA region containing LAT-DNA is known as the "Latency Associated Transcript Region". cite journal
title=Herpes simplex virus latency-associated transcript is a stable intron
journal=Proceedings of the National Academy of Science (USA)
date=1991 February 1
author = Farrell MJ, Dobson AT, Feldman LT
(Free full-text article: [http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=50899&pageindex=1] )]

Apoptosis is the process of normal cell death. In order to maintain a reservoir of latently infected host cells, Herpes virus interferes with apoptosis. HSV-1 LAT expression was once thought to produce interfering "micro-RNA" (miRNA) which suppress production of Human apoptosis-pathway proteins such as TGF-β1 and SMAD3,cite journal|title=Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript|author=Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW|journal=Nature|year=2006|month=May 31|pmid=16738545|doi=10.1038/nature04836(Full-text: [http://www.mstp.northwestern.edu/m1jc_2006-2007/Longnecker_Gupta.pdf] )] but these findings were retracted by the researchers in January 2008. [Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW (Jan 31 2008). Retraction in "Nature" 451 (7178):600.] HHV-8 LAT expression similarly produces miRNAs which suppress production of Thrombospondin-1 protein involved in apoptosis and angiogenesis. cite journal|title=Identification of Cellular Genes Targeted by KSHV-Encoded MicroRNAs|author=Samols MA, Skalsky RL, Maldonado AM, Riva A, Lopez MC, et al.|journal=PLoS Pathogens|volume=3|issue=5(Full-text: [http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.ppat.0030065] ] Expression of LAT also reduces the production of other proteins involved in the apoptosis mechanism, including proteins caspase-8 and caspase-9. ]

LAT expression regulates the activity of the Herpes genome during latent infection. LAT expression results in the suppression of Herpes lytic genes. (Free full-text: [http://www.pnas.org/cgi/content/full/102/44/16055] )] Genetic studies of the LAT-DNA have identified a portion known as a "chromatin insulator" which forms a boundary between activated LAT-DNA and the inactive lytic viral DNA. ]

LAT regulates the expression of lytic genes

HHV Infected Cell Polypeptide 0 (ICP0) gene is expressed very early during lytic infection, and for this reason is called an "immediate-early" Herpes gene. In 1991, Farrell and colleagues report that the 2.0-kb LAT intron terminates at the 5' end with a 750-base antisense RNA complement for the ICP0 gene.

In 2005, Quing-Yin Wang and colleagues from Harvard Medical School concluded, using assays comparing LAT-negative vs. LAT-positive virus strains, that expression of LAT in neurons represses the expression of several lytic gene products, including ICP4 and Thymidine Kinase. LAT expression results in changes to Histones, thus converting portions of viral DNA into a non-productive form known as heterochromatin.

Simian varicella virus (SVV) is a "Varicellovirus" (a Genus of Subfamily "Alphaherpesvirinae") which expresses an HHV LAT homolog known as SVV LAT, and an HHV ICP0 analog known as SVV-ORF61 (Open Reading Frame). SVV LAT is encoded such that it contains an antisense copy of SVV-ORF61 and that expression of SVV LAT during latency downregulates expression of ORF61 and other immediate-early SVV gene products.cite journal|author=Ou Y, Davis KA, Traina-Dorge V, Gray WL|title=Simian varicella virus expresses a latency associated transcript that is antisense to ORF 61 (ICP0) mRNA in neural ganglia of latently infected monkeys|journal=Journal of Virology|date=2007 May 16|pmid=17507490]

LAT DNA contians an activation boundary called a "chromatin insulator"

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 target DNA sequences or "motifs". CTCF binding to DNA may result in formation of transcription-ready euchromatin through the "Histone H3"-acetylating activity which results due to CTCF binding. Acetylation of Histone promotes transcription of DNA to RNA, and then to protein products.]

A March 2006 University of Florida College of Medicine study showed that expression of the Herpes virus genome may be regulated in part by the binding of CTCF to "CTCF-binding motifs". The researchers used sequence analysis and quantitative genomics assays on HHV DNA. In the U. Florida study, the LAT region was found to contain a CTCF-binding region within a 1.5k-bp (base pair) region, and found to contain a "chromatin insulator-like element". A May 2007 study conducted at the Wistar Institute localized the LAT CTCF-binding motif to an 800-bp sequence of the LAT intron, and demonstrated that the region insulated activated LAT chromatin from repressed chromatin that would otherwise produce the lytic protein HHV Infected Cell Polypeptide 0 (ICP0).cite journal|pmid=17267480|title=CTCF-Dependent Chromatin Boundary Element between the Latency-Associated Transcript and ICP0 Promoters in the Herpes Simplex Virus Type 1 Genome|author=Chen Q, Lin L, Smith S, Huang J, Berger SL, Zhou J|journal=Journal of Virology|month=May | year=2007|volume=81|issue=10|pages=5192–201|doi=10.1128/JVI.02447-06]

LAT miRNA interferes with host cell apoptosis

The paper on which this section is based has been retracted recently. Apparently mir-LAT is not a viral miRNA. See http://www.nature.com/nature/journal/v451/n7178/full/nature06621.html for more details

Research has shown that a portion of HSV-1 LAT consists of an interfering micro RNA (miRNA). This miRNA was termed miR-LAT, and shown to downregulate Transforming Growth Factor-β1 (TGF-β1) and SMAD3. These effects block apoptosis, or normal programmed cell death. Further research has shown that HHV-8 LAT produces miRNA which interfere not with expression of TGF-β1 and SMAD3, but reducing the expression of Thrombospondin-1 protein (THBS-1). In turn, down-regulation of THBS-1 reduces production of TGF-β1 and SMAD3, suppressing apoptosis.

Other research showed that the products from the first 4,658 nucleotides of LAT inhibited caspase- 8 and caspase-9 cellular death factors.


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