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'''HHV Latency Associated Transcript''' ('''HHV LAT''') is a length of [[RNA]] which accumulates in cells hosting long-term, or ''latent'', [[Herpesviridae|Human Herpes Virus]] (HHV) infections. The LAT RNA is produced by [[transcription (genetics)|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 lifelong 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 cycle|''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 simplex|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 encodes 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''.<ref name="PMID1846963">{{cite journal|title=Herpes simplex virus latency-associated transcript is a stable intron|journal=Proceedings of the National Academy of Sciences|date=1991-02-01|vauthors=Farrell MJ, Dobson AT, Feldman LT |volume=88|issue=3|pages=790–794|pmid=1846963|doi=10.1073/pnas.88.3.790|pmc=50899|bibcode=1991PNAS...88..790F|doi-access=free}}</ref>

The LAT mainly performs two functions: it suppresses [[apoptosis]] so that latently infected host cells stay alive for the reservoir,<ref name="PMID12491160">{{cite journal|title=Regulation of caspase 8- and caspase 9-induced apoptosis by the herpes simplex virus type 1 latency-associated transcript|vauthors=Henderson G, Peng W, Jin L, Perng GC, Nesburn AB, Wechsler SL, Jones C |date=December 2002|journal=Journal of Neurovirology|pmid=12491160|doi=10.1080/13550280290101085|volume=8|pages=103–111|issue=2}}</ref> and suppresses the expression of lytic genes during latent infection.<ref name="PMID16247011">
{{cite journal|title=Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection|vauthors=Wang QY, Zhou C, Johnson KE, Colgrove RC, Coen DM, Knipe DM |date=1 Nov 2005|journal=Proceedings of the National Academy of Sciences|pmid=16247011|volume=102|issue=44|pages=16055–16059|doi=10.1073/pnas.0505850102|pmc=1266038|doi-access=free|bibcode=2005PNAS..10216055W }}
</ref>

==Lytic gene regulation==
[[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 reported that the 2.0-kb LAT [[intron]] terminates at the 5′ end with a 750-base [[antisense RNA]] complement for the ICP0 gene.<ref name="PMID1846963"/>

In 2005, Qing-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 [[Histone#Histone modifications in chromatin regulation|Histones]], thus converting portions of viral DNA into a non-productive form known
as [[heterochromatin]].<ref name="PMID16247011"/>

[[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.<ref name="OuY_2007">{{cite journal|vauthors=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=2007-05-16|pmid=17507490|volume=81|issue=15|pages=8149–8156|doi=10.1128/JVI.00407-07|pmc=1951321}}</ref>

===Chromatin insulator===
LAT DNA contains an activation boundary between activated LAT-DNA and the inactive lytic viral DNA called a ''chromatin insulator''.<ref name="PMID16474142">{{cite journal|title=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|vauthors=Amelio AL, McAnany PK, Bloom DC |date=March 2006|journal=Journal of Virology|pmid=16474142|doi=10.1128/JVI.80.5.2358-2368.2006|volume=80|pages=2358–2368|issue=5|pmc=1395413}}</ref> [[CTCF|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<ref name="CTCF_HHV"/> 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#Histone modifications in chromatin regulation|''Histone H3''-acetylating]] activity which results due to CTCF binding. Acetylation of Histone promotes [[Transcription (genetics)|transcription]] of DNA to [[RNA]], and then to protein products.<ref name="CTCF_HHV">{{cite web|title=Gene: Ctcf (CCCTC-binding factor) Rattus norvegicus|website=Rat Genome Database|url=https://rgd.mcw.edu/rgdweb/report/gene/main.html?id=621344|access-date=9 December 2020}}</ref>

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".<ref name="PMID16474142"/> 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)]].<ref name="ChenWistar_PMID17267480">{{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|vauthors=Chen Q, Lin L, Smith S, Huang J, Berger SL, Zhou J |journal=Journal of Virology|date=May 2007|volume=81|issue=10|pages=5192–5201|doi=10.1128/JVI.02447-06|pmc=1900208}}</ref>

== Interference of cellular pathways ==
It was alleged that a portion of HSV-1 LAT consists of an interfering [[miRNA|micro RNA]] (miRNA), termed '''mir-LAT'''. This miRNA is shown to downregulate [[Transforming growth factor|Transforming Growth Factor]]-β1 (TGF-β1) and SMAD3. These effects block [[apoptosis]], or normal [[programmed cell death]].<ref name="PMID1678545">{{cite journal|title=Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript|vauthors=Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW |journal=Nature|date=31 May 2006|pmid=16738545|doi=10.1038/nature04836|volume=442|issue=7098|pages=82–85|url=http://www.mstp.northwestern.edu/m1jc_2006-2007/Longnecker_Gupta.pdf|bibcode=2006Natur.442...82G |s2cid=4424780 }}{{Retracted|doi=10.1038/nature06621|pmid=18235505|intentional=yes}}{{Retracted paper|intentional=yes}}</ref> However, although HSV does downregulate apotopsis, the particular miRNA has come to been seen as an experimental artifact, and the paper was consequently retracted.<ref name="apo-retr">{{cite journal |last1=Gupta |first1=A. |last2=Gartner |first2=J. J. |last3=Sethupathy |first3=P. |last4=Hatzigeorgiou |first4=A. G. |last5=Fraser |first5=N. W. |title=Retraction Note to: Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript |journal=Nature |date=31 January 2008 |volume=451 |issue=7178 |pages=600 |doi=10.1038/nature06621|pmid=18235505 |doi-access=free }}</ref>

Other research showed that the products from the first 4,658 nucleotides of LAT inhibited [[caspase]]-8 and caspase-9 cellular death factors.<ref name="PMID12491160"/> Further research has shown that HHV-8 LAT produces RNA 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.<ref name="Samols_2007">{{cite journal|title=Identification of Cellular Genes Targeted by KSHV-Encoded MicroRNAs|author=Samols MA|journal=PLOS Pathogens|volume=3|issue=5|author2=Skalsky RL|author3=Maldonado AM|author4=Riva A|author5=Lopez MC|display-authors=etal|doi=10.1371/journal.ppat.0030065|pages=e65|pmid=17500590|pmc=1876501|year=2007 |doi-access=free }}</ref>

== Protein products ==
The exon parts of LAT-DNA produce two protein products with repeats that are 17 amino acids long, termed HHV latency-related proteins or LR-ORF1 and LR-ORF2. Little is known about these two proteins ({{UniProt|P17588}} and {{UniProt|P17589}} in HHV-1; {{UniProt|K4PBJ5}} and {{UniProt|Q77CA8}} in BHV-1), although the loss of ORF2 in bovine herpesvirus-1 (BHV-1) does appear to interfere with the establishment of latency.<ref>{{cite journal | name-list-style=vanc|last1=Jiang |first1=Y |last2=Inman |first2=M |last3=Zhang |first3=Y |last4=Posadas |first4=NA |last5=Jones |first5=C |title=A mutation in the latency-related gene of bovine herpesvirus 1 inhibits protein expression from open reading frame 2 and an adjacent reading frame during productive infection |journal=Journal of Virology |date=March 2004 |volume=78 |issue=6 |pages=3184–3189 |doi=10.1128/jvi.78.6.3184-3189.2004 |pmid=14990740 |pmc=353721}}</ref> ORF2 has been shown to possess DNA-binding properties. It appears responsible for the inhibition of apotopsis.<ref>{{cite journal | name-list-style=vanc|last1=Pittayakhajonwut |first1=D |last2=Sinani |first2=D |last3=Jones |first3=C |title=A protein (ORF2) encoded by the latency-related gene of bovine herpesvirus 1 interacts with DNA. |journal=Journal of Virology |date=May 2013 |volume=87 |issue=10 |pages=5493–5501 |doi=10.1128/JVI.00193-13 |pmid=23468493 |pmc=3648144}}</ref>

== Footnotes ==
{{Reflist}}

{{DEFAULTSORT:Hhv Latency Associated Transcript}}
[[Category:Herpesviridae]]
[[Category:Viral genes]]
[[Category:Non-coding RNA]]

HHV Latency Associated Transcript - Revision history

imported>RelmC: tagged intentional citation of a retracted source