HHV Latency Associated Transcript
Encyclopedia
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 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.
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, but these findings were retracted by the researchers in January 2008. HHV-8 LAT expression similarly produces miRNAs which suppress production of Thrombospondin
-1 protein involved in apoptosis and angiogenesis
. 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. 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.
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.
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)
.
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.
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
which accumulates in cells hosting long-term, or latent, Human Herpes Virus
Herpesviridae
The Herpesviridae are a large family of DNA viruses that cause 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 , referring to the latent, recurring infections typical of this group of viruses...
(HHV) infections. The LAT RNA is produced by genetic transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
from a certain region of the viral DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. LAT regulates the viral genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
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
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, the consequences of LAT production interfere with these normal processes.
Latency is distinguished from lytic infection
Lytic cycle
The lytic cycle is one of the two cycles of viral reproduction, the other being the lysogenic cycle. The lytic cycle is typically considered the main method of viral replication, since it results in the destruction of the infected cell...
; 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
Herpes simplex
Herpes simplex is a viral disease caused by both Herpes simplex virus type 1 and type 2 . Infection with the herpes virus is categorized into one of several distinct disorders based on the site of infection. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever...
.
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
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
) produced from the 8.3-kb LAT-DNA. The DNA region containing LAT-DNA is known as the Latency Associated Transcript Region.
Apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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
Mirna
Mirna may refer to:geographical entities* Mirna , a river in Istria, Croatia* Mirna , a river in Slovenia, tributary of the river Sava* Mirna , a settlement in the municipality of Mirna in Southeastern Sloveniapeople...
) which suppress production of Human apoptosis-pathway proteins such as TGF-β1
TGF beta
Transforming growth factor beta is a protein that controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, diabetes, Marfan syndrome, and Loeys–Dietz syndrome....
and SMAD3, but these findings were retracted by the researchers in January 2008. HHV-8 LAT expression similarly produces miRNAs which suppress production of Thrombospondin
Thrombospondin
Thrombospondins are secreted proteins with antiangiogenic abilities. TSP was discovered by Nancy L. Baenziger.-Types:The thrombospondins are a family of multifunctional proteins...
-1 protein involved in apoptosis and angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
. Expression of LAT also reduces the production of other proteins involved in the apoptosis mechanism, including proteins caspase
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
-8 and caspase-9.
LAT expression regulates the activity of the Herpes genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
during latent infection. LAT expression results in the suppression of Herpes lytic genes. Genetic studies of the LAT-DNA have identified a portion known as a chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
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)HHV Infected Cell Polypeptide 0 (ICP0)
Human Herpes Virus Infected Cell Polypeptide 0 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 phase of viral gene...
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
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
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
Harvard Medical School
Harvard Medical School is the graduate medical school of Harvard University. It is located in the Longwood Medical Area of the Mission Hill neighborhood of Boston, Massachusetts....
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
Heterochromatin
Heterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin...
.
Simian varicella virus
Simian varicella virus
The Simian Varicella Virus or SVV infects primates and shares clinical, pathological, immunological, and virological features with varicella-zoster virus infection of humans. Monkeys that had been inoculated intratracheally with SVV developed diffuse varicella 10 to 12 days later...
(SVV) is a Varicellovirus
Varicellovirus
Varicellovirus is a genus of Alphaherpesvirinae.The varicellovirus genus contains several closely related viruses, including Varicella zoster virus , the causative agent of chickenpox in humans, and Pseudorabies virus , the causative agent of Aujeszky's disease.- Morphology :As with other...
(a Genus of Subfamily Alphaherpesvirinae
Alphaherpesvirinae
Alphaherpesvirinae is a subfamily of Herpesviridae primarily distinguished by reproducing more quickly than other subfamilies of Herpesviridae. In animal virology the most important herpesviruses belong to the 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.
LAT DNA contains an activation boundary called a chromatin insulator
CCCTC-binding factor (CTCF) is a zinc fingerZinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
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
Euchromatin
Euchromatin is a lightly packed form of chromatin that is rich in gene concentration, and is often under active transcription. Unlike heterochromatin, it is found in both cells with nuclei and cells without nuclei...
through the Histone H3-acetylating activity which results due to CTCF binding. Acetylation of Histone promotes transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of DNA to RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
, and then to protein products.
A March 2006 University of Florida College of Medicine
University of Florida College of Medicine
The University of Florida College of Medicine is the medical school of the University of Florida. It is part of the J. Hillis Miller Health Science Center, with facilities in Gainesville and Jacksonville...
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
Wistar Institute
The Wistar Institute is a biomedical center, with a focus on cancer research and vaccine development. It is located in the University City section of Philadelphia, Pa...
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)
HHV Infected Cell Polypeptide 0 (ICP0)
Human Herpes Virus Infected Cell Polypeptide 0 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 phase of viral gene...
.
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 detailsResearch has shown that a portion of HSV-1 LAT consists of an interfering micro RNA
Mirna
Mirna may refer to:geographical entities* Mirna , a river in Istria, Croatia* Mirna , a river in Slovenia, tributary of the river Sava* Mirna , a settlement in the municipality of Mirna in Southeastern Sloveniapeople...
(miRNA). This miRNA was termed miR-LAT, and shown to downregulate Transforming Growth Factor
Transforming growth factor
Transforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
-β1 (TGF-β1) and SMAD3. These effects block apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, or normal programmed cell death
Programmed cell death
Programmed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
. 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
Thrombospondin
Thrombospondins are secreted proteins with antiangiogenic abilities. TSP was discovered by Nancy L. Baenziger.-Types:The thrombospondins are a family of multifunctional proteins...
-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
Caspase
Caspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
- 8 and caspase-9 cellular death factors.