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 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 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 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.[1]

The LAT mainly performs two functions: it suppresses apoptosis so that latently infected host cells stay alive for the reservoir,[2] and suppresses the expression of lytic genes during latent infection.[3]

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.[1]

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 Histones, thus converting portions of viral DNA into a non-productive form known as heterochromatin.[3]

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.[4]

Chromatin insulator

LAT DNA contains an activation boundary between activated LAT-DNA and the inactive lytic viral DNA called a chromatin insulator.[5] 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 [6] 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.[6]

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".[5] 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).[7]

Interference of cellular pathways

It was alleged that a portion of HSV-1 LAT consists of an interfering micro RNA (miRNA), termed  mir-LAT. This miRNA is shown to downregulate Transforming Growth Factor-β1 (TGF-β1) and SMAD3. These effects block apoptosis, or normal programmed cell death.[8] However, although HSV does downregulate apotopsis, the particular miRNA has come to been seen as an experimental artifact, and the paper was consequently retracted.[9]

Other research showed that the products from the first 4,658 nucleotides of LAT inhibited caspase-8 and caspase-9 cellular death factors.[2] 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.[10]

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 (P17588 and P17589 in HHV-1; K4PBJ5 and Q77CA8 in BHV-1), although the loss of ORF2 in bovine herpesvirus-1 (BHV-1) does appear to interfere with the establishment of latency.[11] ORF2 has been shown to possess DNA-binding properties. It appears responsible for the inhibition of apotopsis.[12]

Footnotes
  1. Farrell MJ, Dobson AT, Feldman LT (1991-02-01). "Herpes simplex virus latency-associated transcript is a stable intron". Proceedings of the National Academy of Sciences. 88 (3): 790–794. Bibcode:1991PNAS...88..790F. doi:10.1073/pnas.88.3.790. PMC 50899. PMID 1846963.
  2. Henderson G, Peng W, Jin L, Perng GC, Nesburn AB, Wechsler SL, Jones C (December 2002). "Regulation of caspase 8- and caspase 9-induced apoptosis by the herpes simplex virus type 1 latency-associated transcript". Journal of Neurovirology. 8 (2): 103–111. doi:10.1080/13550280290101085. PMID 12491160.
  3. Wang QY, Zhou C, Johnson KE, Colgrove RC, Coen DM, Knipe DM (1 Nov 2005). "Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection". Proceedings of the National Academy of Sciences. 102 (44): 16055–16059. Bibcode:2005PNAS..10216055W. doi:10.1073/pnas.0505850102. PMC 1266038. PMID 16247011.
  4. Ou Y, Davis KA, Traina-Dorge V, Gray WL (2007-05-16). "Simian varicella virus expresses a latency associated transcript that is antisense to ORF 61 (ICP0) mRNA in neural ganglia of latently infected monkeys". Journal of Virology. 81 (15): 8149–8156. doi:10.1128/JVI.00407-07. PMC 1951321. PMID 17507490.
  5. Amelio AL, McAnany PK, Bloom DC (March 2006). "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". Journal of Virology. 80 (5): 2358–2368. doi:10.1128/JVI.80.5.2358-2368.2006. PMC 1395413. PMID 16474142.
  6. "Homolog Report: CTCF". Rat Genome Database.
  7. Chen Q, Lin L, Smith S, Huang J, Berger SL, Zhou J (May 2007). "CTCF-Dependent Chromatin Boundary Element between the Latency-Associated Transcript and ICP0 Promoters in the Herpes Simplex Virus Type 1 Genome". Journal of Virology. 81 (10): 5192–5201. doi:10.1128/JVI.02447-06. PMC 1900208. PMID 17267480.
  8. Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW (31 May 2006). "Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript" (PDF). Nature. 442 (7098): 82–85. Bibcode:2006Natur.442...82G. doi:10.1038/nature04836. PMID 16738545. (Retracted)
  9. Gupta, A.; Gartner, J. J.; Sethupathy, P.; Hatzigeorgiou, A. G.; Fraser, N. W. (31 January 2008). "Retraction Note to: Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript". Nature. 451 (7178): 600. doi:10.1038/nature06621. PMID 18235505.
  10. Samols MA, Skalsky RL, Maldonado AM, Riva A, Lopez MC, et al. (2007). "Identification of Cellular Genes Targeted by KSHV-Encoded MicroRNAs". PLOS Pathogens. 3 (5): e65. doi:10.1371/journal.ppat.0030065. PMC 1876501. PMID 17500590.
  11. Jiang Y, Inman M, Zhang Y, Posadas NA, Jones C (March 2004). "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 of Virology. 78 (6): 3184–3189. doi:10.1128/jvi.78.6.3184-3189.2004. PMC 353721. PMID 14990740.
  12. Pittayakhajonwut D, Sinani D, Jones C (May 2013). "A protein (ORF2) encoded by the latency-related gene of bovine herpesvirus 1 interacts with DNA". Journal of Virology. 87 (10): 5493–5501. doi:10.1128/JVI.00193-13. PMC 3648144. PMID 23468493.
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