HHV Latency Associated Transcript

Last updated

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.

Contents

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. 1 2 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. 1 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. 1 2 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. 1 2 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. 1 2 "Gene: Ctcf (CCCTC-binding factor) Rattus norvegicus". Rat Genome Database. Retrieved 9 December 2020.
  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. S2CID   4424780. (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.

Related Research Articles

Epstein–Barr virus Virus of the herpes family

The Epstein–Barr virus (EBV), formally called Human gammaherpesvirus 4, is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus.

<i>Hepadnaviridae</i> Family of viruses

Hepadnaviridae is a family of viruses. Humans, apes, and birds serve as natural hosts. There are currently 18 species in this family, divided among 5 genera. Its best-known member is hepatitis B virus. Diseases associated with this family include: liver infections, such as hepatitis, hepatocellular carcinomas, and cirrhosis. It is the sole family in the order Blubervirales.

<i>Papillomaviridae</i> Family of viruses

Papillomaviridae is a family of non-enveloped DNA viruses whose members are known as papillomaviruses. Several hundred species of papillomaviruses, traditionally referred to as "types", have been identified infecting all carefully inspected mammals, but also other vertebrates such as birds, snakes, turtles and fish. Infection by most papillomavirus types, depending on the type, is either asymptomatic or causes small benign tumors, known as papillomas or warts. Papillomas caused by some types, however, such as human papillomaviruses 16 and 18, carry a risk of becoming cancerous.

Kaposis sarcoma-associated herpesvirus Species of virus

Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is Human gammaherpesvirus 8, or HHV-8 in short. Like other herpesviruses, its informal names are used interchangeably with its formal ICTV name. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary effusion lymphoma, HHV-8-associated multicentric Castleman's disease and KSHV inflammatory cytokine syndrome. It is one of seven currently known human cancer viruses, or oncoviruses. Even after so many years of discovery of KSHV/HHV8, there is no known cure for KSHV associated tumorigenesis.

Virus latency

Virus latency is the ability of a pathogenic virus to lie dormant within a cell, denoted as the lysogenic part of the viral life cycle. A latent viral infection is a type of persistent viral infection which is distinguished from a chronic viral infection. Latency is the phase in certain viruses' life cycles in which, after initial infection, proliferation of virus particles ceases. However, the viral genome is not eradicated. The virus can reactivate and begin producing large amounts of viral progeny without the host becoming reinfected by new outside virus, and stays within the host indefinitely.

Human herpesvirus 6 Informal grouping of viruses which caused human herpesvirus 6 Infection

Human herpesvirus 6 (HHV-6) is the common collective name for human betaherpesvirus 6A (HHV-6A) and human betaherpesvirus 6B (HHV-6B). These closely related viruses are two of the nine known human herpesviruses, herpesviruses that have humans as their primary host.

<i>Herpesviridae</i> Family of DNA viruses

Herpesviridae is a large family of DNA viruses that cause infections and certain diseases in animals, including humans. The members of this family are also known as herpesviruses. The family name is derived from the Greek word herpein 'to creep', referring to spreading cutaneous lesions, usually involving blisters, seen in flares of herpes simplex 1, herpes simplex 2 and herpes zoster (shingles). In 1971, the International Committee on the Taxonomy of Viruses (ICTV) established Herpesvirus as a genus with 23 viruses among four groups. As of 2020, 115 species are recognized, all but one of which are in one of the three subfamilies. Herpesviruses can cause both latent and lytic infections.

HHV Infected Cell Polypeptide 0

Human Herpes Virus (HHV) Infected Cell Polypeptide 0 (ICP0) is a protein, encoded by the DNA of herpes viruses. It is produced by herpes viruses during the earliest stage of infection, when the virus has recently entered the host cell; this stage is known as the immediate-early or α ("alpha") phase of viral gene expression. During these early stages of infection, ICP0 protein is synthesized and transported to the nucleus of the infected host cell. Here, ICP0 promotes transcription from viral genes, disrupts structures in the nucleus known as nuclear dots or promyelocytic leukemia (PML) nuclear bodies, and alters the expression of host and viral genes in combination with a neuron specific protein. At later stages of cellular infection, ICP0 relocates to the cell cytoplasm to be incorporated into new virion particles.

Herpes simplex virus Species of virus

Herpes simplex virus1 and 2, also known by their taxonomical names Human alphaherpesvirus 1 and Human alphaherpesvirus 2, are two members of the human Herpesviridae family, a set of new viruses that produce viral infections in the majority of humans. Both HSV-1 and HSV-2 are common and contagious. They can be spread when an infected person begins shedding the virus.

<i>Gammaherpesvirinae</i> Subfamily of viruses

Gammaherpesvirinae is a subfamily of viruses in the order Herpesvirales and in the family Herpesviridae. Viruses in Gammaherpesvirinae are distinguished by reproducing at a more variable rate than other subfamilies of Herpesviridae. Mammals serve as natural hosts. There are 43 species in this subfamily, divided among 7 genera with three species unassigned to a genus. Diseases associated with this subfamily include: HHV-4: infectious mononucleosis. HHV-8: Kaposi's sarcoma.

HHV Capsid Portal Protein, or HSV-1 UL-6 protein, is the protein which forms a cylindrical portal in the capsid of Herpes simplex virus (HSV-1). The protein is commonly referred to as the HSV-1 UL-6 protein because it is the transcription product of Herpes gene UL-6.

The latency-associated nuclear antigen (LANA-1) or latent nuclear antigen , is a Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein initially found by Moore and colleagues as a speckled nuclear antigen present in primary effusion lymphoma cells that reacts with antibodies from patients with KS. It is the most immunodominant KSHV protein identified by Western-blotting as 222–234 kDa double bands migrate slower than the predicted molecular weight. LANA has been suspected of playing a crucial role in modulating viral and cellular gene expression. It is commonly used as an antigen in blood tests to detect antibodies in persons that have been exposed to KSHV.

The Epstein–Barr virus nuclear antigen 2 (EBNA-2) is one of the six EBV viral nuclear proteins expressed in latently infected B lymphocytes is a transactivator protein. EBNA2 is involved in the regulation of latent viral transcription and contributes to the immortalization of EBV infected cells. EBNA2 acts as an adapter molecule that binds to cellular sequence-specific DNA-binding proteins, JK recombination signal-binding protein (RBP-JK), and PU.1 as well as working with multiple members of the RNA polymerase II transcription complex.

ICP8, the herpes simplex virus type-1 single-strand DNA-binding protein, is one of seven proteins encoded in the viral genome of HSV-1 that is required for HSV-1 DNA replication. It is able to anneal to single-stranded DNA (ssDNA) as well as melt small fragments of double-stranded DNA (dsDNA); its role is to destabilize duplex DNA during initiation of replication. It differs from helicases because it is ATP- and Mg2+-independent. In cells infected with HSV-1, the DNA in those cells become colocalized with ICP8.

Single-stranded binding protein

Single-stranded binding proteins (SSBs) are a class of proteins that have been identified in both viruses and organisms from bacteria to humans.

David M. Knipe is the Higgins Professor of Microbiology and Molecular Genetics and interim Co-Chair in the Department of Microbiology and Immunobiology at the Harvard Medical School in Boston, Massachusetts and co-chief editor of the reference book Fields Virology. He had previously served as Chair of the Program in Virology at Harvard Medical School from 2004 through 2016.

BZLF1, also known as Zta, EB1, is an immediate-early viral gene of the Epstein–Barr virus (EBV) of the Herpes Virus Family, which induces cancers and infects primarily the B-cells of 95% of the human population. This gene produces the expression of other EBV genes in other stages of disease progression, and is involved in converting the virus from the latent to the lytic form.

Epigenetics of human herpesvirus latency

Human Herpes Viruses, also known as HHVs, are part of a family of DNA viruses that cause several diseases in humans. One of the most notable functions of this virus family is their ability to enter a latent phase and lay dormant within animals for extended periods of time. The mechanism that controls this is very complex because expression of viral proteins during latency is decreased a great deal, meaning that the virus must have transcription of its genes repressed. There are many factors and mechanisms that control this process and epigenetics is one way this is accomplished. Epigenetics refers to persistent changes in expression patterns that are not caused by changes to the DNA sequence. This happens through mechanisms such as methylation and acetylation of histones, DNA methylation, and non-coding RNAs (ncRNA). Altering the acetylation of histones creates changes in expression by changing the binding affinity of histones to DNA, making it harder or easier for transcription machinery to access the DNA. Methyl and acetyl groups can also act as binding sites for transcription factors and enzymes that further modify histones or alter the DNA itself.

HSV epigenetics is the epigenetic modification of herpes simplex virus (HSV) genetic code.

Helicoverpa zea nudivirus 2 is an enveloped, rod-shaped, nonoccluded, double stranded DNA (dsDNA) sexually transmitted virus whose natural host is the corn earworm moth. At about 440 by 90 nm, it is the causative agent of the only sexually transmitted viral disease of any insect. It was originally identified in a colony of corn earworm moths established and maintained in Stoneville, Mississippi, U.S. and was found to be responsible for the sterility of those infected.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.