Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''
Human alphaherpesvirus 1
''Human alphaherpesvirus 1'' (HHV-1) is a species of virus in the genus ''Simplexvirus'', subfamily ''Alphaherpesvirinae'', family ''Herpesviridae'', and order ''Herpesvirales''.
Evolution
The ''Human alphaherpesvirus 1'' virus can be classifi ...
'' and ''
Human alphaherpesvirus 2'', are two members of the
human ''Herpesviridae'' family, a set of viruses that produce
viral infections
A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells.
Structural Characteristics
Basic structural characteristics, ...
in the majority of
human
Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, culture, ...
s.
Both HSV-1 and HSV-2 are very common and
contagious
Contagious may refer to:
* Contagious disease
Literature
* Contagious (magazine), a marketing publication
* ''Contagious'' (novel), a science fiction thriller novel by Scott Sigler
Music
Albums
*''Contagious'' (Peggy Scott-Adams album), 1997
* ...
. They can be spread when an infected person begins
shedding the
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's 1 ...
.
As of 2016, about 67% of the world population under the age of 50 had HSV-1. In the United States, about 47.8% and 11.9% are estimated to have HSV-1 and HSV-2, respectively, though actual
prevalence
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
may be much higher. Because it can be transmitted through any intimate contact, it is one of the most common
sexually transmitted infection
Sexually transmitted infections (STIs), also referred to as sexually transmitted diseases (STDs) and the older term venereal diseases, are infections that are Transmission (medicine), spread by Human sexual activity, sexual activity, especi ...
s.
Symptoms
Many of those who are infected ''never'' develop symptoms.
Symptoms, when they occur, may include watery
blister
A blister is a small pocket of body fluid (lymph, serum, plasma, blood, or pus) within the upper layers of the skin, usually caused by forceful rubbing (friction), burning, freezing, chemical exposure or infection. Most blisters are filled wi ...
s in the
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
or
mucous membranes
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
of the mouth, lips, nose, genitals,
or eyes (
herpes simplex keratitis
Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.
It begins with infection of epithelial cells on the surface of the eye and retrograde infection of nerves serving the cornea ...
). Lesions heal with a
scab characteristic of herpetic disease. Sometimes, the viruses cause mild or atypical symptoms during outbreaks. However, they can also cause more troublesome forms of
herpes simplex
Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected.
Oral herpes involves the face or mouth. It may result in small blisters in groups often called cold ...
. As
neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by hiding from the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
in the
cell
Cell most often refers to:
* Cell (biology), the functional basic unit of life
Cell may also refer to:
Locations
* Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
bodies of
neurons
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
, particularly in sensory ganglia. 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 neuron's
axon
An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action po ...
to the skin, where virus replication and shedding occur and may cause new sores.
Transmission
HSV-1 and HSV-2 are transmitted by contact with an infected person who has reactivations of the virus.
HSV 1 and HSV-2 are periodically shed, most often asymptomatically.
In a study of people with first-episode genital HSV-1 infection from 2022, genital shedding of HSV-1 was detected on 12% of days at 2 months and declined significantly to 7% of days at 11 months. Most genital shedding was asymptomatic; genital and oral lesions and oral shedding were rare.
Most sexual transmissions of HSV-2 occur during periods of ''asymptomatic shedding''.
Asymptomatic reactivation means that the virus causes atypical, subtle, or hard-to-notice symptoms that are not identified as an active herpes infection, so acquiring the virus is possible even if no active HSV blisters or sores are present. In one study, daily genital swab samples detected HSV-2 at a median of 12–28% of days among those who had an outbreak, and 10% of days among those with asymptomatic infection (no prior outbreaks), with many of these episodes occurring ''without'' visible outbreak ("subclinical shedding").
In another study, 73 subjects were randomized to receive
valaciclovir
Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken ...
1 g daily or placebo for 60 days each in a two-way
crossover design
In medicine, a crossover study or crossover trial is a longitudinal study in which subjects receive a sequence of different treatments (or exposures). While crossover studies can be observational studies, many important crossover studies are con ...
. A daily swab of the genital area was self-collected for HSV-2 detection by polymerase chain reaction, to compare the effect of valaciclovir versus placebo on asymptomatic viral shedding in immunocompetent, HSV-2 seropositive subjects without a history of symptomatic genital herpes infection. The study found that valaciclovir significantly reduced shedding during subclinical days compared to placebo, showing a 71% reduction; 84% of subjects had no shedding while receiving valaciclovir versus 54% of subjects on placebo. About 88% of patients treated with valaciclovir had no recognized signs or symptoms versus 77% for placebo.
For HSV-2, subclinical shedding may account for most of the transmission.
[ Studies on discordant partners (one infected with HSV-2, one not) show that the transmission rate is approximately 5 per 10,000 sexual contacts. Atypical symptoms are often attributed to other causes, such as a ]yeast infection
Candidiasis is a fungal infection due to any type of '' Candida'' (a type of yeast). When it affects the mouth, in some countries it is commonly called thrush. Signs and symptoms include white patches on the tongue or other areas of the mouth ...
. HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as kissing
A kiss is the touch or pressing of one's lips against another person or an object. Cultural connotations of kissing vary widely. Depending on the culture and context, a kiss can express sentiments of love, passion, romance, sexual attraction, ...
and oral sex
Oral sex, sometimes referred to as oral intercourse, is sexual activity involving the stimulation of the genitalia of a person by another person using the mouth (including the lips, tongue, or teeth) and the throat. Cunnilingus is oral sex per ...
. Historically HSV-2 was primarily a sexually transmitted infection, but rates of HSV-1 genital infections have been increasing for the last few decades.
Both viruses may also be transmitted vertically during childbirth. However, the risk of transmission is minimal if the mother has no symptoms nor exposed blisters during delivery. The risk is considerable when the mother is infected with the virus for the ''first'' time during late pregnancy, reflecting high viral load. While most viral STD's can not be transmitted through objects as the virus dies quickly outside of the body, HSV has proven to survive for up to 4,5 hours on surfaces and can be transmitted through use of towels, toothbrushes, cups, cutlery etc.
Herpes simplex viruses can affect areas of skin exposed to contact with an infected person (although shaking hands with an infected person does not transmit this disease). An example of this is herpetic whitlow
A herpetic whitlow is a lesion ( whitlow), typically on a finger or thumb, caused by the herpes simplex virus (HSV). Occasionally infection occurs on the toes or on the nail cuticle. Herpes whitlow can be caused by infection by HSV-1 or HSV-2. HSV ...
, which is a herpes infection on the fingers. This condition was common for dental surgeon
A dentist, also known as a dental surgeon, is a health care professional who specializes in dentistry (the diagnosis, prevention, management, and treatment of diseases and conditions of the oral cavity and other aspects of the craniofacial com ...
s prior to the routine use of gloves when conducting treatment on patients. Genital infection of HSV-2 increases the risk of acquiring HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
.
Virology
HSV has been a model virus for many studies in molecular biology. For instance, one of the first functional promoters in eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s was discovered in HSV (of the thymidine kinase
Thymidine kinase is an enzyme, a phosphotransferase (a kinase): 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Cert ...
gene) and the virion protein VP16 is one of the most-studied transcriptional activators
A transcriptional activator is a protein (transcription factor) that increases transcription of a gene or set of genes. Activators are considered to have ''positive'' control over gene expression, as they function to promote gene transcription and ...
.
Viral Structure
Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large, double-stranded, linear DNA genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
encased within an icosahedral
In geometry, an icosahedron ( or ) is a polyhedron with 20 faces. The name comes and . The plural can be either "icosahedra" () or "icosahedrons".
There are infinitely many non- similar shapes of icosahedra, some of them being more symmetrica ...
protein cage called the capsid
A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may ...
, which is wrapped in a lipid bilayer
The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many vir ...
called the envelope
An envelope is a common packaging item, usually made of thin, flat material. It is designed to contain a flat object, such as a letter or card.
Traditional envelopes are made from sheets of paper cut to one of three shapes: a rhombus, a sh ...
. The envelope is joined to the capsid by means of a tegument. This complete particle is known as the virion
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsky's ...
. HSV-1 and HSV-2 each contain at least 74 genes (or open reading frames
In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readin ...
, 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 HSV-1 and HSV-2 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 (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryo ...
of the infected host. Immediate early gene
Immediate early genes (IEGs) 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 ...
s, which encode proteins for example ICP22 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
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s involved in DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
and the production of certain envelope
An envelope is a common packaging item, usually made of thin, flat material. It is designed to contain a flat object, such as a letter or card.
Traditional envelopes are made from sheets of paper cut to one of three shapes: a rhombus, a sh ...
glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
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.
Cellular Entry
Entry of HSV into a host cell involves several glycoprotein
Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
s on the surface of the enveloped virus binding to their transmembrane receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell signaling by receiving (binding to) ex ...
s on the cell surface. Many of these receptors are then pulled inwards by the cell, which is thought to open a ring of three gHgL heterodimers stabilizing a compact conformation of the gB glycoprotein, so that it springs out and punctures the cell membrane. The envelope covering the virus particle then fuses with the cell membrane, creating a pore through which the contents of the viral envelope 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. Interactions of these molecules then form a stable entry pore through which the viral envelope contents are introduced to the host cell. The virus can also be endocytosed after binding to the receptors, and the fusion could occur at the endosome
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
. In electron micrographs, the outer leaflets of the viral and cellular lipid bilayers have been seen merged; this hemifusion may be on the usual path to entry or it may usually be an arrested state more likely to be captured than a transient entry mechanism.
In the case of a herpes virus, initial interactions occur when two viral envelope glycoprotein called glycoprotein C (gC) and glycoprotein B (gB) bind to a cell surface polysaccharide
Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wa ...
called heparan sulfate
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...
. Next, the major receptor binding protein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors. These cell receptors include herpesvirus entry mediator (HVEM
Herpesvirus entry mediator (HVEM), also known as tumor necrosis factor receptor superfamily member 14 (TNFRSF14), is a human cell surface receptor of the TNF-receptor superfamily.
Nomenclature
This protein was originally known as herpesvirus ent ...
), nectin
Nectins and Nectin-like molecules (Necl) 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 ju ...
-1 and 3-O sulfated heparan sulfate. The nectin receptors usually produce cell-cell adhesion, to provide a strong point of attachment for the virus 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 may result in a hemifusion state. gB interaction with the gH/gL complex creates an entry pore for the viral capsid. gB interacts with glycosaminoglycan
Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...
s on the surface of the host cell.
Genetic Inoculation
After the viral capsid enters the cellular cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, it is transported to the cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
. 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 12 copies of portal protein, UL6, arranged as a ring; the proteins contain a leucine zipper
A leucine zipper (or leucine scissors) is a common three-dimensional structural motif in proteins. They were first described by Landschulz and collaborators in 1988 when they found that an enhancer binding protein had a very characteristic 30-amin ...
sequence of amino acids
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
, which allow them to adhere to each other.[
] Each icosahedral
In geometry, an icosahedron ( or ) is a polyhedron with 20 faces. The name comes and . The plural can be either "icosahedra" () or "icosahedrons".
There are infinitely many non- similar shapes of icosahedra, some of them being more symmetrica ...
capsid contains a single portal, located in one vertex
Vertex, vertices or vertexes may refer to:
Science and technology Mathematics and computer science
*Vertex (geometry), a point where two or more curves, lines, or edges meet
* Vertex (computer graphics), a data structure that describes the positio ...
.[
][
]
The DNA exits the capsid in a single linear segment.
Immune Evasion
HSV evades the immune system through interference with MHC class I antigen presentation
Antigen presentation is a vital immune process that is essential for T cell immune response triggering. Because T cells recognize only fragmented antigens displayed on cell surfaces, antigen processing must occur before the antigen fragment, n ...
on the cell surface, by blocking the transporter associated with antigen processing
Transporter associated with antigen processing (TAP) protein complex belongs to the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to nascent MHC class I molecules.
...
(TAP) induced by the secretion of ICP-47 by HSV. In the host cell, TAP transports digested viral antigen epitope peptides from the cytosol to the endoplasmic reticulum, allowing these epitopes to be combined with MHC class I molecules and presented on the surface of the cell. Viral epitope presentation with MHC class I is a requirement for activation of cytotoxic T-lymphocytes (CTLs), the major effectors of the cell-mediated immune response against virally-infected cells. ICP-47 prevents initiation of a CTL-response against HSV, allowing the virus to survive for a protracted period in the host. HSV usually produces cytopathic effect (CPE) within 24–72 hours post-infection in permissive cell lines which is observed by classical plaque formation. However, HSV-1 clinical isolates have also been reported that did not show any CPE in Vero and A549 cell cultures over several passages with low level of virus protein expression. Probably these HSV-1 isolates are evolving towards a more "cryptic" form to establish chronic infection thereby unravelling yet another strategy to evade the host immune system, besides neuronal latency.
Replication
Following infection of a cell, a cascade of herpes virus proteins, called immediate-early, early, and late, is produced. Research using flow cytometry
Flow cytometry (FC) is a technique used to detect and measure physical and chemical characteristics of a population of cells or particles.
In this process, a sample containing cells or particles is suspended in a fluid and injected into the flo ...
on another member of the herpes virus family, Kaposi's sarcoma-associated herpesvirus
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 herpesvir ...
, 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
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
. 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
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
, helps in viral replication, and regulates gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
of viral proteins. The viral genome immediately travels to the nucleus, but the VHS protein remains in the cytoplasm.
The late proteins form the capsid and the receptors on the surface of the virus. Packaging of the viral particles — including the genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
, core and the capsid - occurs in the nucleus of the cell. Here, concatemer
A concatemer is a long continuous DNA molecule that contains multiple copies of the same DNA sequence linked in series. These polymeric molecules are usually copies of an entire genome linked end to end and separated by ''cos'' sites (a protein bi ...
s of the viral genome are separated by cleavage and are placed into 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. The virus acquires its final envelope by budding into cytoplasmic vesicles
Vesicle may refer to:
; In cellular biology or chemistry
* Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane
* Synaptic vesicle
; In human embryology
* Vesicle (embryology), bulge-like features o ...
.
Latent Infection
HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia. HSV-1 tends to reside in the trigeminal ganglia
A trigeminal ganglion (or Gasserian ganglion, or semilunar ganglion, or Gasser's ganglion) is the sensory ganglion at the base of each of the two trigeminal nerves (CN V), occupying a cavity ( Meckel's cave) in the dura mater, covering the trige ...
, while HSV-2 tends to reside in the sacral ganglia
The sacral ganglia are paravertebral ganglia of the sympathetic trunk.:39 As the sympathetic trunk heads inferiorly down the sacrum, it turns medially. There are generally four or five sacral ganglia. In addition to gray rami communicantes, the gan ...
, but these are historical tendencies only. During latent infection of a cell, HSVs express latency-associated transcript (LAT) RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
. LAT regulates 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 nonlatency. Whether or not recurrences are symptomatic, viral shedding occurs to infect a new host.
A protein found in neurons 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 In the context of gene regulation: transactivation is the increased rate of gene expression triggered either by biological processes or by artificial means, through the expression of an intermediate transactivator protein.
In the context of rece ...
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
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 ...
dissociates NRSF from the ''ICP4'' gene and thus prevents silencing of the viral DNA.
Genome
The HSV genome spans about 150,000 bp and consists of two unique segments, named unique long (UL) and unique short (US), as well as terminal inverted repeats found to the two ends of them named repeat long (RL) and repeat short (RS). There are also minor "terminal redundancy" (α) elements found on the further ends of RS. The overall arrangement is RL-UL-RL-α-RS-US-RS-α with each pair of repeats inverting each other. The whole sequence is then encapsuled in a terminal direct repeat. The long and short parts each have their own origins of replication, with OriL located between UL28 and UL30 and OriS located in a pair near the RS. As the L and S segments can be assembled in any direction, they can be inverted relative to each other freely, forming various linear isomers.
Gene expression
HSV genes are expressed in 3 temporal classes: immediate early (IE or α), early (E or ß) and late (γ) genes. However, the progression of viral gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
is rather gradual than in clearly distinct stages. Immediate early genes are transcribed right after infection and their gene products activate transcription of the early genes. Early gene products help to replicate the viral DNA. Viral DNA replication
In molecular biology, DNA replication is the biological process of producing two identical replicas of DNA from one original DNA molecule. DNA replication occurs in all living organisms acting as the most essential part for biological inheritanc ...
, in turn, stimulates the expression of the late genes, encoding the structural proteins.
Transcription of the immediate early (IE) genes begins right after virus DNA enters the nucleus. All virus genes are transcribed by host RNA polymerase II
RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukaryo ...
. Although host proteins are sufficient for virus transcription, viral proteins are necessary for the transcription of certain genes. For instance, VP16 plays an important role in IE transcription and the virus particle apparently brings it into the host cell, so that it does not need to be produced first. Similarly, the IE proteins RS1 (ICP4), UL54 (ICP27), and ICP0 promote the transcription of the early (E) genes. Like IE genes, early gene promoters contain binding sites for cellular transcription factors. One early protein, ICP8, is necessary for both transcription of late genes and DNA replication.
Later in the life cycle of HSV, expression of immediate early and early genes is shut down. This is mediated by specific virus proteins, e.g. ICP4, which represses itself by binding to elements in its own promoter. As a consequence, the down-regulation of ICP4 levels leads to a reduction of early and late gene expression, as ICP4 is important for both.
Importantly, HSV shuts down host cell RNA, DNA and protein synthesis to direct cellular resources to virus production. First, the virus protein vhs induces the degradation of existing mRNAs
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein.
mRNA is created during the p ...
early in infection. Other viral genes impede cellular transcription and translation. For instance, ICP27 inhibits RNA splicing
RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...
, so that virus mRNAs (which are usually not spliced) gain an advantage over host mRNAs. Finally, virus proteins destabilize certain cellular proteins involved in the host cell cycle
The cell cycle, or cell-division cycle, is the series of events that take place in a cell that cause it to divide into two daughter cells. These events include the duplication of its DNA (DNA replication) and some of its organelles, and sub ...
, so that both cell division and host cell DNA replication disturbed in favor of virus replication.
Evolution
The herpes simplex 1 genomes can be classified into six clade
A clade (), also known as a monophyletic group or natural group, is a group of organisms that are monophyletic – that is, composed of a common ancestor and all its lineal descendants – on a phylogenetic tree. Rather than the English term, ...
s. Four of these occur in East Africa
East Africa, Eastern Africa, or East of Africa, is the eastern subregion of the African continent. In the United Nations Statistics Division scheme of geographic regions, 10-11-(16*) territories make up Eastern Africa:
Due to the historical ...
, one in East Asia
East Asia is the eastern region of Asia, which is defined in both geographical and ethno-cultural terms. The modern states of East Asia include China, Japan, Mongolia, North Korea, South Korea, and Taiwan. China, North Korea, South Korea and ...
and one in Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
and North America
North America is a continent in the Northern Hemisphere and almost entirely within the Western Hemisphere. It is bordered to the north by the Arctic Ocean, to the east by the Atlantic Ocean, to the southeast by South America and the Car ...
. This suggests that the virus may have originated in East Africa. The most recent common ancestor
In biology and genetic genealogy, the most recent common ancestor (MRCA), also known as the last common ancestor (LCA) or concestor, of a set of organisms is the most recent individual from which all the organisms of the set are descended. The ...
of the Eurasian strains appears to have evolved ~60,000 years ago. The East Asian HSV-1 isolates have an unusual pattern that is currently best explained by the two waves of migration responsible for the peopling of Japan
Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the north ...
.
Herpes simplex 2 genomes can be divided into two groups: one is globally distributed and the other is mostly limited to sub Saharan Africa
Sub-Saharan Africa is, geographically, the area and regions of the continent of Africa that lies south of the Sahara. These include West Africa, East Africa, Central Africa, and Southern Africa. Geopolitically, in addition to the African co ...
. The globally distributed genotype
The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a ...
has undergone four ancient recombinations with herpes simplex 1. It has also been reported that HSV-1 and HSV-2 can have contemporary and stable recombination events in hosts simultaneously infected with both pathogens. All of the cases are HSV-2 acquiring parts of the HSV-1 genome, sometimes changing parts of its antigen epitope in the process.
The mutation rate has been estimated to be ~1.38×10−7 substitutions/site/year. In clinical setting, the mutations in either the thymidine kinase gene or DNA polymerase gene has caused resistance to aciclovir
Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following tra ...
. However, most of the mutations occur in the thymidine kinase gene rather than the DNA polymerase gene.
Another analysis has estimated the mutation rate in the herpes simplex 1 genome to be 1.82×10−8 nucleotide substitution per site per year. This analysis placed the most recent common ancestor of this virus ~710,000 years ago.
Herpes simplex 1 and 2 diverged about .[
]
Treatment
Similar to other herpesviridae
''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 ''ἕρπει ...
, the herpes simplex viruses establish latent lifelong infection, and thus cannot be eradicated from the body with current treatments.
Treatment usually involves general-purpose antiviral drug
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...
s that interfere with viral replication, reduce the physical severity of outbreak-associated lesions, and lower the chance of transmission to others. Studies of vulnerable patient populations have indicated that daily use of antivirals such as aciclovir
Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following tra ...
and valaciclovir can reduce reactivation rates. The extensive use of antiherpetic drugs has led to the development of some drug resistance
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is ...
, which in turn may lead to treatment failure. Therefore, new sources of drugs are broadly investigated to address the problem. In January 2020, a comprehensive review article was published that demonstrated the effectiveness of natural products as promising anti-HSV drugs. Pyrithione
Pyrithione is the common name of an organosulfur compound with molecular formula , chosen as an abbreviation of pyridinethione, and found in the Persian shallot. It exists as a pair of tautomers, the major form being the thione 1-hydroxy-2(1''H ...
, a zinc ionophore
In chemistry, an ionophore () is a chemical species that reversibly binds ions. Many ionophores are lipid-soluble entities that transport ions across the cell membrane. Ionophores catalyze ion transport across hydrophobic membranes, such as liq ...
, has shown antiviral activity against herpes simplex.
Alzheimer's disease
In 1979, it was reported that there is a possible link between HSV-1 and Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, in people with the epsilon4 allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
of the gene APOE
Apolipoprotein E (APOE) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular disease.
APOE belongs to a family of fat-binding proteins called apolipoproteins. ...
. 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
A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, su ...
, which may lead to the development of Alzheimer's disease. This research identifies HSVs as the pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
most clearly linked to the establishment of Alzheimer's. According to a study done in 1997, without the presence of the gene allele
An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.
::"The chro ...
, HSV-1 does not appear to cause any neurological damage or increase the risk of Alzheimer's. However, a more recent prospective study published in 2008 with a cohort of 591 people showed a statistically significant difference between patients with antibodies indicating recent reactivation of HSV and those without these antibodies in the incidence of Alzheimer's disease, without direct correlation to the APOE-epsilon4 allele.
The trial had a small sample of patients who did not have the antibody at baseline, so the results should be viewed as highly ''uncertain''. In 2011, Manchester University scientists showed that treating HSV1-infected cells with antiviral agents decreased the accumulation of β-amyloid
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which ...
and tau protein
The tau proteins (abbreviated from tubulin associated unit) are a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintaining ...
and also decreased HSV-1 replication.
A 2018 retrospective study from Taiwan
Taiwan, officially the Republic of China (ROC), is a country in East Asia, at the junction of the East and South China Seas in the northwestern Pacific Ocean, with the People's Republic of China (PRC) to the northwest, Japan to the nort ...
on 33,000 patients found that being infected with herpes simplex virus increased the risk of dementia 2.56 times (95% CI: 2.3-2.8) in patients not receiving anti-herpetic medications (2.6 times for HSV-1 infections and 2.0 times for HSV-2 infections). However, HSV-infected patients who were receiving anti-herpetic medications (acyclovir
Aciclovir (ACV), also known as acyclovir, is an antiviral medication. It is primarily used for the treatment of herpes simplex virus infections, chickenpox, and shingles. Other uses include prevention of cytomegalovirus infections following t ...
, famciclovir
Famciclovir is a guanosine analogue antiviral drug used for the treatment of various herpesvirus infections, most commonly for herpes zoster (shingles). It is a prodrug form of penciclovir with improved oral bioavailability. Famciclovir is mark ...
, ganciclovir
Ganciclovir, sold under the brand name Cytovene among others, is an antiviral medication used to treat cytomegalovirus (CMV) infections.
Ganciclovir was patented in 1980 and approved for medical use in 1988.
Medical use
Ganciclovir is indicated ...
, idoxuridine
Idoxuridine is an anti-herpesvirus antiviral drug.
It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the iodine atom added to the uracil component blocks base pairin ...
, penciclovir
Penciclovir is a guanosine analogue antiviral drug used for the treatment of various herpesvirus infections. It is a nucleoside analogue which exhibits low toxicity and good selectivity. Because penciclovir is absorbed poorly when given orally (b ...
, tromantadine
Tromantadine is an antiviral medicine used to treat herpes simplex virus. It is available in a topical gel under trade names Viru-Merz and Viru-Merz Serol. Its performance is similar to aciclovir.
Like rimantadine, amantadine, and adapromine, ...
, valaciclovir
Valaciclovir, also spelled valacyclovir, is an antiviral medication used to treat outbreaks of herpes simplex or herpes zoster (shingles). It is also used to prevent cytomegalovirus following a kidney transplant in high risk cases. It is taken ...
, or valganciclovir
Valganciclovir, sold under the brand name Valcyte among others, is an antiviral medication used to treat cytomegalovirus (CMV) infection in those with HIV/AIDS or following organ transplant. It is often used long term as it only suppresses rath ...
) showed no elevated risk of dementia compared to patients uninfected with HSV.
Multiplicity reactivation
Multiplicity reactivation (MR) is the process by which viral genomes containing inactivating damage interact within an infected cell to form a viable viral genome. MR was originally discovered with the bacterial virus bacteriophage T4, but was subsequently also found with pathogenic viruses including influenza virus, HIV-1, adenovirus simian virus 40, vaccinia virus, reovirus, poliovirus and herpes simplex virus.
When HSV particles are exposed to doses of a DNA damaging agent that would be lethal in single infections, but are then allowed to undergo multiple infection (i.e. two or more viruses per host cell), MR is observed. Enhanced survival of HSV-1 due to MR occurs upon exposure to different DNA damaging agents, including methyl methanesulfonate
Methyl methanesulfonate (MMS), also known as methyl mesylate, is an alkylating agent and a carcinogen. It is also a suspected reproductive toxicant, and may also be a skin/sense organ toxicant. It is used in cancer treatment.cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
and has been extensively clinically tested to assess its oncolytic
An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viru ...
(cancer killing) ability. Interim overall survival data from Amgen
Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was esta ...
's phase 3 trial of a genetically attenuated herpes virus suggests efficacy against melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
.
Use in neuronal connection tracing
Herpes simplex virus is also used as a transneuronal tracer defining connections among neurons by virtue of traversing synapses.
Other related outcomes
HSV-2 the most common cause of Mollaret's meningitis
Mollaret's meningitis is a recurrent or chronic inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. Since Mollaret's meningitis is a recurrent, benign (non-cancerous), aseptic meningitis, ...
. HSV-1 can lead to potentially fatal cases of herpes simplex encephalitis
Herpesviral encephalitis, or herpes simplex encephalitis (HSE), is encephalitis due to herpes simplex virus. It is estimated to affect at least 1 in 500,000 individuals per year, and some studies suggest an incidence rate of 5.9 cases per 100,00 ...
. Herpes simplex viruses have also been studied in the central nervous system disorders such as multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
, but research has been conflicting and inconclusive.
Following a diagnosis of genital herpes simplex infection, patients may develop an episode of profound depression. In addition to offering antiviral medication to alleviate symptoms and shorten their duration, physicians must also address the mental health impact of a new diagnosis. Providing information on the very high prevalence
In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
of these infections, their effective treatments, and future therapies in development may provide hope to patients who are otherwise demoralized.
Research
There exist commonly used vaccines to some herpesviruses, such as the veterinary vaccine HVT/LT (Turkey herpesvirus vector laryngotracheitis vaccine). However, it prevents atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
(which histologically
Histology,
also known as microscopic anatomy or microanatomy, is the branch of biology which studies the microscopic anatomy of biological tissues. Histology is the microscopic counterpart to gross anatomy, which looks at larger structures vis ...
mirrors atherosclerosis in humans) in target animals vaccinated.
The only human vaccines available for herpesviruses are for Varicella zoster virus
Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...
, given to children around their first birthday to prevent chickenpox
Chickenpox, also known as varicella, is a highly contagious disease caused by the initial infection with varicella zoster virus (VZV). The disease results in a characteristic skin rash that forms small, itchy blisters, which eventually scab ...
(varicella), or to adults to prevent an outbreak of shingles
Shingles, also known as zoster or herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. ...
(herpes zoster) . There is, however, no human vaccine for herpes simplex viruses. As of 2022, there are active pre-clinical and clinical studies underway on herpes simplex in humans; vaccines are being developed for both treatment and prevention.
References
External links
*
Herpes simplex: Host viral protein interactions: A database of HSV-1 interacting host proteins
3D macromolecular structures of the Herpes simplex virus archived in the EM Data Bank(EMDB)
{{DEFAULTSORT:Herpes Simplex Virus
Simplexviruses
Unaccepted virus taxa
Sexually transmitted diseases and infections
Articles containing video clips