Herpes simplex virus
Encyclopedia
Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as Human herpes virus 1 and 2 (HHV-1 and -2), are two members of the herpes virus
family, Herpesviridae
, that infect human
s. Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious
. They can be spread when an infected person is producing and shedding
the virus.
Symptoms of herpes simplex virus infection
include watery blister
s in the skin
or mucous membranes of the mouth, lips or genitals. Lesions heal with a scab
characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as neurotropic and neuroinvasive viruses
, HSV-1 and -2 persist in the body by becoming latent and hiding from the immune system
in the cell
bodies of nerve
s. After the initial or primary infection, some infected people experience sporadic episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the nerve's axon
to the skin, where virus replication and shedding occur and cause new sores.
Both viruses may also be transmitted vertically during childbirth, although the real risk is very low. The risk of infection is minimal if the mother has no symptoms or exposed blisters during delivery. The risk is considerable when the mother gets the virus for the first time during late pregnancy.
Symptoms resulting from primary infection with HSV are usually much more severe than subsequent outbreaks, as the body has not had a chance to produce antibodies. This first outbreak of oral herpes (cold sores) carries a low (≈1%) risk of developing aseptic meningitis
.
genome
encased within an icosahedral
protein cage called the capsid
, which is wrapped in a lipid bilayer
called the envelope. The envelope is joined to the capsid by means of a tegument
. This complete particle is known as the virion. HSV-1 and HSV-2 each contain at least 74 genes (or open-reading frames, ORFs) within their genomes, although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs. These genes encode a variety of proteins involved in forming the capsid, tegument and envelope of the virus, as well as controlling the replication and infectivity of the virus. These genes and their functions are summarized in the table below.
The genomes of HSV1 and HSV2 are complex and contain two unique regions called the long unique region (UL) and the short unique region (US). Of the 74 known ORFs, UL contains 56 viral genes, whereas US contains only 12. Transcription of HSV genes is catalyzed by RNA polymerase II
of the infected host. Immediate early gene
s, which encode proteins that regulate the expression of early and late viral genes, are the first to be expressed following infection. Early gene
expression follows, to allow the synthesis of enzyme
s involved in DNA replication
and the production of certain envelope
glycoprotein
s. Expression of late genes occurs last; this group of genes predominantly encode proteins that form the virion particle.
Five proteins from (UL) form the viral capsid; UL6
, UL18, UL35, UL38 and the major capsid protein UL19.
Entry of HSV into the host cell involves interactions of several glycoprotein
s on the surface of the enveloped virus, with receptors on the surface of the host cell. The envelope covering the virus particle, when bound to specific receptors on the cell surface, will fuse with the host cell membrane and create an opening, or pore, through which the virus enters the host cell.
The sequential stages of HSV entry are analogous to those of other viruses
. At first, complementary receptors on the virus and the cell surface bring the viral and cell membranes into proximity. In an intermediate state, the two membranes begin to merge, forming a hemifusion state. Finally, a stable entry pore is formed through which the viral envelope contents are introduced to the host cell.
In the case of a herpes virus, initial interactions occur when a viral envelope glycoprotein called glycoprotein C (gC) binds to a cell surface particle called heparan sulfate
. A second glycoprotein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. These include herpesvirus entry mediator(HVEM
), nectin
-1 and 3-O sulfated heparan sulfate. The receptor provides a strong, fixed attachment to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other glycoproteins embedded in the viral envelope to interact with other cell surface molecules.
Once bound to the HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L (gL), which form a complex. The interaction of these membrane proteins results in the hemifusion state. Afterward, gB interaction with the gH/gL complex creates an entry pore for the viral capsid. Glycoprotein B interacts with glycosaminoglycan
s on the surface of the host cell.
, it is transported to the cell nucleus
. Once attached to the nucleus at a nuclear entry pore, the capsid ejects its DNA contents via the capsid portal. The capsid portal is formed by twelve copies of portal protein, UL6, arranged as a ring; the proteins contain a leucine zipper
sequence of amino acids which allow them to adhere to each other. Each icosahedral capsid contains a single portal, located in one vertex
.
The DNA exits the capsid in a single linear segment.
molecule before it is transported via the golgi apparatus for recognition by CD8+ CTLs
on the cell surface. ICP-47 disrupts this integrity, preventing the capture of cytosolic proteins for CTL recognition and thus evades CTL destruction.
, and late, are produced. Research using flow cytometry
on another member of the herpes virus family, Kaposi's sarcoma-associated herpesvirus
, indicates the possibility of an additional lytic stage
, delayed-late. These stages of lytic infection, particularly late lytic, are distinct from the latency stage. In the case of HSV-1, no protein products are detected during latency, whereas they are detected during the lytic cycle.
The early proteins transcribed are used in the regulation of genetic replication of the virus. On entering the cell, an α-TIF protein joins the viral particle and aids in immediate-early
transcription
. The virion host shutoff protein (VHS or UL41) is very important to viral replication. This enzyme shuts off protein synthesis in the host, degrades host mRNA
, helps in viral replication, and regulates gene expression
of viral proteins. The viral genome immediately travels to the nucleus but the VHS protein remains in the cytoplasm.
The late proteins are used in to form the capsid and the receptors on the surface of the virus. Packaging of the viral particles — including the genome
, core and the capsid
- occurs in the nucleus of the cell. Here, concatemers of the viral genome are separated by cleavage and are placed into pre-formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. The primary envelope is acquired by budding into the inner nuclear membrane of the cell. This then fuses with the outer nuclear membrane releasing a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into cytoplasmic vesicles
.
. HSV-1 tends to reside in the trigeminal ganglia
, while HSV-2 tends to reside in the sacral ganglia
, but note that these are tendencies only, not fixed behavior. During such latent infection of a cell, HSVs express Latency Associated Transcript (LAT) RNA
. LAT is known to regulate the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences or "outbreaks" characteristic of non-latency. Whether or not recurrences are noticeable (symptomatic) or not, viral shedding occurs to produce further infections (usually in a new host, if any). A protein found in neuron
s may bind to herpes virus DNA and regulate latency
. Herpes virus DNA contains a gene for a protein called ICP4, which is an important transactivator
of genes associated with lytic infection in HSV-1. Elements surrounding the gene for ICP4 bind a protein known as the human neuronal protein Neuronal Restrictive Silencing Factor (NRSF) or human Repressor Element Silencing Transcription Factor (REST). When bound to the viral DNA elements, histone deacetylation
occurs atop the ICP4 gene sequence to prevent initiation of transcription from this gene, thereby preventing transcription of other viral genes involved in the lytic cycle. Another HSV protein reverses the inhibition of ICP4 protein synthesis. ICP0
dissociates NRSF from the ICP4 gene and thus prevents silencing of the viral DNA.
The virus can be reactivated by illnesses such as colds and influenza, eczema, emotional and physical stress, gastric upset, fatigue or injury, by menstruation and possibly exposure to bright sunlight.
Herpes viruses establish lifelong infections and the virus cannot currently be eradicated from the body. Treatment usually involves general-purpose antiviral drug
s that interfere with viral replication, reducing the physical severity of outbreak-associated lesions and lowering the chance of transmission to others. Studies of vulnerable patient populations have indicated that daily use of antivirals such as acyclovir and valacyclovir can reduce reactivation rates.
In vitro research has indicated that Aloe Vera
may be effective against genital herpes.
-epsilon4 allele carriers), a possible link between HSV-1 (i.e., the virus that causes cold sores or oral herpes) and Alzheimer’s disease was reported in 1979. HSV-1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease. The virus interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimer's disease. This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s. Without the presence of the gene allele, HSV-1 does not appear to cause any neurological damage or increase the risk of Alzheimer’s.
Many more Alzheimer's disease susceptibility genes, including the major players APOE, clusterin, complement receptor 1 and PICALM are involved in the herpes simplex life cycle as curated in this database
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
family, Herpesviridae
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...
, that infect human
Human
Humans are the only living species in the Homo genus...
s. Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...
. They can be spread when an infected person is producing and shedding
Viral shedding
Viral shedding refers to the successful reproduction, expulsion, and host-cell infection caused by virus progeny. Once replication has been completed and the host cell is exhausted of all resources in making viral progeny, the viruses may begin to leave the cell by several methods.The term is used...
the virus.
Symptoms of herpes simplex virus infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
include watery blister
Blister
A blister is a small pocket of fluid within the upper layers of the skin, typically caused by forceful rubbing , burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid called serum or plasma...
s in the skin
Skin
-Dermis:The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis is tightly connected to the epidermis by a basement membrane. It also harbors many Mechanoreceptors that provide the sense of touch and heat...
or mucous membranes of the mouth, lips or genitals. Lesions heal with a scab
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as neurotropic and neuroinvasive viruses
Neurotropic virus
A neurotropic virus is a virus which is capable of infecting nerve cells, or which does so preferentially. Such viruses thereby largely evade the usual immune response—which acts only within the blood system.- Terminology :...
, HSV-1 and -2 persist in the body by becoming latent and hiding from 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...
in the cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
bodies of nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s. After the initial or primary infection, some infected people experience sporadic episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the nerve's axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
to the skin, where virus replication and shedding occur and cause new sores.
Transmission
HSV-1 and -2 are transmitted from contact with an infectious area of the skin during reactivations of the virus. Although less likely, the herpes viruses can be transmitted during latency. Transmission is likely to occur during symptomatic reactivation of the virus that causes visible and typical skin sores. Asymptomatic reactivation means that the virus causes atypical, subtle or hard to notice symptoms that are not identified as an active herpes infection. Atypical symptoms are often attributed to other causes such as a yeast infection. HSV-1 is usually acquired orally during childhood, but may also be sexually transmitted. HSV-2 is primarily a sexually transmitted infection but rates of HSV-1 genital infections are increasing.Both viruses may also be transmitted vertically during childbirth, although the real risk is very low. The risk of infection is minimal if the mother has no symptoms or exposed blisters during delivery. The risk is considerable when the mother gets the virus for the first time during late pregnancy.
Symptoms resulting from primary infection with HSV are usually much more severe than subsequent outbreaks, as the body has not had a chance to produce antibodies. This first outbreak of oral herpes (cold sores) carries a low (≈1%) risk of developing aseptic meningitis
Aseptic meningitis
Aseptic meningitis, or sterile meningitis, is a condition in which the layers lining the brain, meninges, become inflamed and a pyogenic bacterial source is not to blame. Meningitis is diagnosed on a history of characteristic symptoms and certain examination findings...
.
Viral structure
Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large double-stranded, linear DNADNA
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...
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....
encased within an icosahedral
Icosahedron
In geometry, an icosahedron is a regular polyhedron with 20 identical equilateral triangular faces, 30 edges and 12 vertices. It is one of the five Platonic solids....
protein cage called the capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
, which is wrapped in a lipid bilayer
Lipid bilayer
The lipid bilayer is a thin membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around cells. The cell membrane of almost all living organisms and many viruses are made of a lipid bilayer, as are the membranes surrounding the cell nucleus...
called the envelope. The envelope is joined to the capsid by means of a tegument
Viral tegument
A viral tegument or tegument, more commonly known as a viral matrix, is a cluster of proteins that lines the space between the envelope and nucleocapsid of all herpesviruses. The tegument generally contains proteins that aid in viral DNA replication and evasion of the immune response, typically...
. This complete particle is known as the virion. HSV-1 and HSV-2 each contain at least 74 genes (or open-reading frames, ORFs) within their genomes, although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs. These genes encode a variety of proteins involved in forming the capsid, tegument and envelope of the virus, as well as controlling the replication and infectivity of the virus. These genes and their functions are summarized in the table below.
The genomes of HSV1 and HSV2 are complex and contain two unique regions called the long unique region (UL) and the short unique region (US). Of the 74 known ORFs, UL contains 56 viral genes, whereas US contains only 12. Transcription of HSV genes is catalyzed by RNA polymerase II
RNA polymerase II
RNA polymerase II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA. A 550 kDa complex of 12 subunits, RNAP II is the most studied type of RNA polymerase...
of the infected host. Immediate early gene
Immediate early gene
Immediate early genes are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized...
s, which encode proteins that regulate the expression of early and late viral genes, are the first to be expressed following infection. Early gene
Early protein
The classification of viral proteins as early proteins or late proteins depends on their relationship with genome replication. While many viruses are described as expressing early and late proteins, this definition of these terms is commonly reserved for class I DNA viruses...
expression follows, to allow the synthesis of enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s involved in DNA replication
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and the production of certain envelope
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s. Expression of late genes occurs last; this group of genes predominantly encode proteins that form the virion particle.
Five proteins from (UL) form the viral capsid; UL6
HHV capsid portal protein
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 . 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 Herpes viral DNA enters and exits...
, UL18, UL35, UL38 and the major capsid protein UL19.
Cellular entry
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s on the surface of the enveloped virus, with receptors on the surface of the host cell. The envelope covering the virus particle, when bound to specific receptors on the cell surface, will fuse with the host cell membrane and create an opening, or pore, through which the virus enters the host cell.
The sequential stages of HSV entry are analogous to those of other viruses
Viral entry
Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variation among viruses, the generalities are quite similar...
. At first, complementary receptors on the virus and the cell surface bring the viral and cell membranes into proximity. In an intermediate state, the two membranes begin to merge, forming a hemifusion state. Finally, a stable entry pore is formed through which the viral envelope contents are introduced to the host cell.
In the case of a herpes virus, initial interactions occur when a viral envelope glycoprotein called glycoprotein C (gC) binds to a cell surface particle called heparan sulfate
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
. A second glycoprotein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. These include herpesvirus entry mediator(HVEM
TNFRSF14
Tumor necrosis factor receptor superfamily member 14 is a protein that in humans is encoded by the TNFRSF14 gene. It is also known as "herpesvirus entry mediator" .-Interactions:...
), nectin
Nectin
Nectins and Nectin-like molecules are families of cellular adhesion molecules involved in Ca2+-independent cellular adhesion.Nectins are ubiquitously expressed and have adhesive roles in a wide range of tissues such as the adherens junction of epithelia or the chemical synapse of the neuronal...
-1 and 3-O sulfated heparan sulfate. The receptor provides a strong, fixed attachment to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other glycoproteins embedded in the viral envelope to interact with other cell surface molecules.
Once bound to the HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L (gL), which form a complex. The interaction of these membrane proteins results in the hemifusion state. Afterward, gB interaction with the gH/gL complex creates an entry pore for the viral capsid. Glycoprotein B interacts with glycosaminoglycan
Glycosaminoglycan
Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...
s on the surface of the host cell.
Genetic inoculation
After the viral capsid enters the cellular cytoplasmCytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, it is transported to the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
. Once attached to the nucleus at a nuclear entry pore, the capsid ejects its DNA contents via the capsid portal. The capsid portal is formed by twelve copies of portal protein, UL6, arranged as a ring; the proteins contain a leucine zipper
Leucine zipper
A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...
sequence of amino acids which allow them to adhere to each other. Each icosahedral capsid contains a single portal, located in one vertex
Vertex (geometry)
In geometry, a vertex is a special kind of point that describes the corners or intersections of geometric shapes.-Of an angle:...
.
The DNA exits the capsid in a single linear segment.
Immune evasion
HSV evades the immune system through interference with MHC class I presentation of antigen on the cell surface. It achieves this through blockade of the TAP transporter induced by the secretion of ICP-47 by HSV. TAP maintains the integrity of the MHC class IMHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
molecule before it is transported via the golgi apparatus for recognition by CD8+ CTLs
Cytotoxic T cell
A cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...
on the cell surface. ICP-47 disrupts this integrity, preventing the capture of cytosolic proteins for CTL recognition and thus evades CTL destruction.
Replication
Following infection of a cell, herpes virus proteins, called immediate-early, earlyEarly protein
The classification of viral proteins as early proteins or late proteins depends on their relationship with genome replication. While many viruses are described as expressing early and late proteins, this definition of these terms is commonly reserved for class I DNA viruses...
, and late, are produced. Research using flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
on another member of the herpes virus family, Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus is one of seven currently known human cancer viruses, or oncoviruses. It is also the eighth human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses is HHV-8. Like other herpesviruses, its informal name is used...
, indicates the possibility of an additional lytic stage
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...
, delayed-late. These stages of lytic infection, particularly late lytic, are distinct from the latency stage. In the case of HSV-1, no protein products are detected during latency, whereas they are detected during the lytic cycle.
The early proteins transcribed are used in the regulation of genetic replication of the virus. On entering the cell, an α-TIF protein joins the viral particle and aids in immediate-early
Early protein
The classification of viral proteins as early proteins or late proteins depends on their relationship with genome replication. While many viruses are described as expressing early and late proteins, this definition of these terms is commonly reserved for class I DNA viruses...
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...
. The virion host shutoff protein (VHS or UL41) is very important to viral replication. This enzyme shuts off protein synthesis in the host, degrades host mRNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
, helps in viral replication, and regulates gene expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of viral proteins. The viral genome immediately travels to the nucleus but the VHS protein remains in the cytoplasm.
The late proteins are used in to form the capsid and the receptors on the surface of the virus. Packaging of the viral particles — including the 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....
, core and the capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
- occurs in the nucleus of the cell. Here, concatemers of the viral genome are separated by cleavage and are placed into pre-formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. The primary envelope is acquired by budding into the inner nuclear membrane of the cell. This then fuses with the outer nuclear membrane releasing a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into cytoplasmic vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
.
Latent infection
HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural gangliaGanglion
In anatomy, a ganglion is a biological tissue mass, most commonly a mass of nerve cell bodies. Cells found in a ganglion are called ganglion cells, though this term is also sometimes used to refer specifically to retinal ganglion cells....
. HSV-1 tends to reside in the trigeminal ganglia
Trigeminal ganglion
The trigeminal ganglion is a sensory ganglion of the trigeminal nerve that occupies a cavity in the dura mater, covering the trigeminal impression near the apex of the petrous part of the temporal bone.-Relations:It is somewhat crescentic in shape, with its convexity...
, while HSV-2 tends to reside in the sacral ganglia
Sacral ganglia
The sacral ganglia are paravertebral ganglia of the sympathetic trunk. As the sympathetic trunk heads inferiorly down the sacrum, it turns medially. There are generally four or five sacral ganglia...
, but note that these are tendencies only, not fixed behavior. During such latent infection of a cell, HSVs express Latency Associated Transcript (LAT) RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. LAT is known to regulate the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows subsequent, usually symptomatic, periodic recurrences or "outbreaks" characteristic of non-latency. Whether or not recurrences are noticeable (symptomatic) or not, viral shedding occurs to produce further infections (usually in a new host, if any). A protein found in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s may bind to herpes virus DNA and regulate latency
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...
. Herpes virus DNA contains a gene for a protein called ICP4, which is an important transactivator
Transactivation
In molecular biology and genetics, transactivation is an increased rate of gene expression triggered either by biological processes or by artificial means.- Natural transactivation :...
of genes associated with lytic infection in HSV-1. Elements surrounding the gene for ICP4 bind a protein known as the human neuronal protein Neuronal Restrictive Silencing Factor (NRSF) or human Repressor Element Silencing Transcription Factor (REST). When bound to the viral DNA elements, histone deacetylation
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
occurs atop the ICP4 gene sequence to prevent initiation of transcription from this gene, thereby preventing transcription of other viral genes involved in the lytic cycle. Another HSV protein reverses the inhibition of ICP4 protein synthesis. 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...
dissociates NRSF from the ICP4 gene and thus prevents silencing of the viral DNA.
The virus can be reactivated by illnesses such as colds and influenza, eczema, emotional and physical stress, gastric upset, fatigue or injury, by menstruation and possibly exposure to bright sunlight.
Viral genome
| The open reading frames (ORFs) of HSV-1 | |||||
| Gene | Protein | Function/description | Gene | Protein | Function/description |
| UL1 | Glycoprotein Glycoprotein Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending... L http://www.uniprot.org/uniprot/P10185 |
Surface and membrane | UL38 | UL38; VP19C http://www.uniprot.org/uniprot/P32888 | Capsid assembly and DNA maturation |
| UL2 | UL2 http://www.uniprot.org/uniprot/P10186 | Uracil-DNA glycosylase Uracil-DNA glycosylase Uracil-DNA glycosylase, also known as UNG or UDG, is a human gene though orthologs exist ubiquitously among prokaryotes and eukaryotes and even in some DNA viruses. The first uracil DNA-glycosylase was isolated from Escherichia coli.... |
UL39 | UL39 http://www.uniprot.org/uniprot/P08543 | Ribonucleotide reductase Ribonucleotide reductase Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms... (Large subunit) |
| UL3 | UL3 http://www.uniprot.org/uniprot/P10187 | unknown | UL40 | UL40 http://www.uniprot.org/uniprot/P06474 | Ribonucleotide reductase (Small subunit) |
| UL4 | UL4 http://www.uniprot.org/uniprot/P10188 | unknown | UL41 | UL41; VHS http://www.uniprot.org/uniprot/P10225 | Tegument protein; Virion host shutoff |
| UL5 | UL5 http://www.expasy.org/uniprot/Q2MGV2 | DNA replication DNA replication DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule... |
UL42 | UL42 http://www.expasy.org/uniprot/Q4H1G9 | DNA polymerase DNA polymerase A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand.... processivity factor |
| UL6 | Portal protein UL-6 HHV capsid portal protein 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 . 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 Herpes viral DNA enters and exits... |
Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid. | UL43 | UL43 http://www.expasy.org/uniprot/P10227 | Membrane protein |
| UL7 | UL7 http://www.expasy.org/uniprot/P10190 | Virion maturation | UL44 | Glycoprotein C http://www.expasy.org/uniprot/P10228 | Surface and membrane |
| UL8 | UL8 http://www.expasy.org/uniprot/P10192 | DNA helicase/primase complex-associated protein | UL45 | UL45 http://www.expasy.org/uniprot/P10229 | Membrane protein; C-type lectin |
| UL9 | UL9 http://www.expasy.org/uniprot/P10193 | Replication origin Origin of replication The origin of replication is a particular sequence in a genome at which replication is initiated. This can either be DNA replication in living organisms such as prokaryotes and eukaryotes, or RNA replication in RNA viruses, such as double-stranded RNA viruses... -binding protein |
UL46 | VP11/12 http://www.expasy.org/uniprot/P08314 | Tegument proteins |
| UL10 | Glycoprotein M http://www.expasy.org/uniprot/P04288 | Surface and membrane | UL47 | UL47; VP13/14 http://www.expasy.org/uniprot/P10231 | Tegument protein |
| UL11 | UL11 http://www.expasy.org/uniprot/P04289 | virion exit and secondary envelopment | UL48 | VP16 (Alpha-TIF) http://www.expasy.org/uniprot/P04486 | Virion maturation; activate IEGs Immediate early gene Immediate early genes are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized... by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'. |
| UL12 | UL12 http://www.expasy.org/uniprot/Q68978 | Alkaline exonuclease Exonuclease Exonucleases are enzymes that work by cleaving nucleotides one at a time from the end of a polynucleotide chain. A hydrolyzing reaction that breaks phosphodiester bonds at either the 3’ or the 5’ end occurs. Its close relative is the endonuclease, which cleaves phosphodiester bonds in the middle ... |
UL49 | UL49A http://www.expasy.org/uniprot/O09800 | Envelope protein |
| UL13 | UL13 http://www.expasy.org/uniprot/Q9QNF2 | Serine Serine Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:... -threonine Threonine Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar... protein kinase Protein kinase A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins... |
UL50 | UL50 http://www.expasy.org/uniprot/P10234 | dUTP diphosphatase DUTP diphosphatase In enzymology, a dUTP diphosphatase is an enzyme that catalyzes the chemical reactionThus, the two substrates of this enzyme are dUTP and H2O, whereas its two products are dUMP and diphosphate.... |
| UL14 | UL14 http://www.expasy.org/uniprot/P04291 | Tegument Viral tegument A viral tegument or tegument, more commonly known as a viral matrix, is a cluster of proteins that lines the space between the envelope and nucleocapsid of all herpesviruses. The tegument generally contains proteins that aid in viral DNA replication and evasion of the immune response, typically... protein |
UL51 | UL51 http://www.expasy.org/uniprot/P10234 | Tegument protein |
| UL15 | Terminase http://www.expasy.org/uniprot/P04295 | Processing and packaging of DNA | UL52 | UL52 http://www.expasy.org/uniprot/P10236 | DNA helicase/primase complex protein |
| UL16 | UL16 http://www.expasy.org/uniprot/P10200 | Tegument protein | UL53 | Glycoprotein K http://www.expasy.org/uniprot/P68333 | Surface and membrane |
| UL17 | UL17 http://www.expasy.org/uniprot/P10201 | Processing and packaging DNA | UL54 | IE63; ICP27 http://www.expasy.org/uniprot/P10238 | Transcriptional regulation |
| UL18 | VP23 http://www.expasy.org/uniprot/P10202 | Capsid Capsid A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic... protein |
UL55 | UL55 http://www.expasy.org/uniprot/P10239 | Unknown |
| UL19 | VP5 http://www.expasy.org/uniprot/P06491 | Major capsid protein | UL56 | UL56 http://www.expasy.org/uniprot/P10240 | Unknown |
| UL20 | UL20 http://www.expasy.org/uniprot/P10204 | Membrane protein | US1 | ICP22; IE68 http://www.expasy.org/uniprot/P04485 | Viral replication |
| UL21 | UL21 http://www.expasy.org/uniprot/P10205 | Tegument protein | US2 | US2 http://www.expasy.org/uniprot/P06485 | Unknown |
| UL22 | Glycoprotein H http://www.expasy.org/uniprot/P06477 | Surface and membrane | US3 | US3 http://www.expasy.org/uniprot/P04413 | Serine/threonine-protein kinase |
| UL23 | Thymidine kinase Thymidine kinase Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, . It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2... http://www.expasy.org/uniprot/O55259 |
Peripheral to DNA replication | US4 | Glycoprotein G http://www.expasy.org/uniprot/P06484 | Surface and membrane |
| UL24 | UL24 http://www.expasy.org/uniprot/P10208 | unknown | US5 | Glycoprotein J http://www.expasy.org/uniprot/P06480 | Surface and membrane |
| UL25 | UL25 http://www.expasy.org/uniprot/P10209 | Processing and packaging DNA | US6 | Glycoprotein D http://www.expasy.org/uniprot/A1Z0Q5 | Surface and membrane |
| UL26 | P40; VP24; VP22A http://www.expasy.org/uniprot/P10210 | Capsid protein | US7 | Glycoprotein I http://www.expasy.org/uniprot/P06487 | Surface and membrane |
| UL27 | Glycoprotein B Herpesvirus Glycoprotein B Herpesvirus glycoprotein B is a viral glycoprotein that is involved in the viral cell entry of Herpes simplex virus . Herpesviruses have an envelope and an outer lipid bilayer which contains twelve surface glycoproteins... http://www.expasy.org/uniprot/A1Z0P5 |
Surface and membrane | US8 | Glycoprotein E http://www.expasy.org/uniprot/Q703F0 | Surface and membrane |
| UL28 | ICP18.5 http://www.expasy.org/uniprot/P10212 | Processing and packaging DNA | US9 | US9 http://www.expasy.org/uniprot/P06481 | Tegument protein |
| UL29 | UL29; ICP8 http://www.expasy.org/uniprot/Q2MGU6 | Major DNA-binding protein | US10 | US10 http://www.expasy.org/uniprot/P06486 | Capsid/Tegument protein |
| UL30 | DNA polymerase DNA polymerase A DNA polymerase is an enzyme that helps catalyze in the polymerization of deoxyribonucleotides into a DNA strand. DNA polymerases are best known for their feedback role in DNA replication, in which the polymerase "reads" an intact DNA strand as a template and uses it to synthesize the new strand.... http://www.expasy.org/uniprot/Q4ACM2 |
DNA replication | US11 | US11; Vmw21 http://www.expasy.org/uniprot/P56958 | Binds DNA and RNA |
| UL31 | UL31 http://www.expasy.org/uniprot/Q25BX0 | Nuclear matrix protein | US12 | ICP47; IE12 http://www.expasy.org/uniprot/P03170 | Inhibits MHC class I MHC class I MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body... pathway by preventing binding of antigen to TAP Transporter associated with antigen processing Transporter associated with antigen processing is a member of the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum , where they bind to nascent MHC class I molecules.... |
| UL32 | UL32 http://www.expasy.org/uniprot/P10216 | Envelope Viral envelope Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells... glycoprotein Glycoprotein Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending... |
RS1 | ICP4; IE175 http://www.expasy.org/uniprot/P08392 | Major transcriptional activator. Essential for progression beyond the immediate-early phase of infection. IEG Immediate early gene Immediate early genes are genes which are activated transiently and rapidly in response to a wide variety of cellular stimuli. They represent a standing response mechanism that is activated at the transcription level in the first round of response to stimuli, before any new proteins are synthesized... transcription repressor. |
| UL33 | UL33 http://www.expasy.org/uniprot/P10217 | Processing and packaging DNA | 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... |
ICP0; IE110; α0 http://www.expasy.org/uniprot/P08393 | E3 ubiquitin Ubiquitin Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction... ligase that activates viral gene transcription and counteracts the interferon Interferon Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to... response |
| UL34 | UL34 http://www.expasy.org/uniprot/P10218 | Inner nuclear membrane protein | LRP1 | LRP1 http://www.expasy.org/uniprot/P17588 | Latency-related protein |
| UL35 | VP26 http://www.expasy.org/uniprot/P10219 | Capsid protein | LRP2 | LRP2 http://www.expasy.org/uniprot/P17589 | Latency-related protein |
| UL36 | UL36 http://www.expasy.org/uniprot/P10220 | Large tegument protein | RL1 | RL1; ICP34.5 http://www.expasy.org/uniprot/O12396 | Neurovirulence factor. Antagonizes PKR Protein kinase R Protein kinase RNA-activated also known as protein kinase R , interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 is an enzyme that in humans is encoded by the EIF2AK2 gene.PKR protects against viral... by de-phosphorylating eIF4a. |
| UL37 | UL37 http://www.expasy.org/uniprot/P10216 | Capsid assembly | LAT HHV Latency Associated Transcript HHV Latency Associated Transcript is a length of RNA which accumulates in cells hosting long-term, or latent, Human Herpes Virus infections. The LAT RNA is produced by genetic transcription from a certain region of the viral DNA... |
none http://www.expasy.org/uniprot/Q69079 | Latency-associated transcript |
Treatment and vaccine development
- For more details on treatment of herpes simplex virus, see Herpes simplex.
- For more information on vaccines, see Herpes simplex vaccine
Herpes viruses establish lifelong infections and the virus cannot currently be eradicated from the body. Treatment usually involves general-purpose antiviral drug
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...
s that interfere with viral replication, reducing the physical severity of outbreak-associated lesions and lowering the chance of transmission to others. Studies of vulnerable patient populations have indicated that daily use of antivirals such as acyclovir and valacyclovir can reduce reactivation rates.
In vitro research has indicated that Aloe Vera
Aloe vera
Aloe vera, pronounced , also known as the true aloe or medicinal aloe, is a species of succulent plant in the genus Aloe that is believed to have originated in the Sudan. Aloe vera grows in arid climates and is widely distributed in Africa, India, Nepal and other arid areas.The species is...
may be effective against genital herpes.
Connection between facial sores and Alzheimer's disease
In the presence of a certain gene variation (APOEApolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...
-epsilon4 allele carriers), a possible link between HSV-1 (i.e., the virus that causes cold sores or oral herpes) and Alzheimer’s disease was reported in 1979. HSV-1 appears to be particularly damaging to the nervous system and increases one’s risk of developing Alzheimer’s disease. The virus interacts with the components and receptors of lipoproteins, which may lead to the development of Alzheimer's disease. This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s. Without the presence of the gene allele, HSV-1 does not appear to cause any neurological damage or increase the risk of Alzheimer’s.
Many more Alzheimer's disease susceptibility genes, including the major players APOE, clusterin, complement receptor 1 and PICALM are involved in the herpes simplex life cycle as curated in this database