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Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as human herpesvirus 1 and 2 (HHV-1 and HHV-2), are two members of the herpesvirus family, , that infect . Both HSV-1 (which produces most ) and HSV-2 (which produces most genital herpes) are ubiquitous and . They can be spread when an infected person is producing and
In simple terms, herpes simplex 1 is most commonly known as a "cold sore", while herpes simplex 2 is the one known by the public as "herpes", or "genital herpes". According to the World Health Organization 67% of the world population under the age of 50 have HSV-1.
Symptoms of herpes simplex virus
include watery
of the mouth, lips, nose or genitals. Lesions heal with a
characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, they can also cause more troublesome forms of . As , HSV-1 and -2 persist in the body by becoming latent and hiding from the
bodies of . After the initial or primary infection, some infected people experience
episodes of viral reactivation or outbreaks. In an outbreak, the virus in a nerve cell becomes active and is transported via the neuron's
to the skin, where virus replication and shedding occur and cause new sores. It is one of the most common sexually transmitted infections.
HSV-1 and -2 are transmitted by contact with an infected person who has reactivations of the virus. Herpes simplex virus (HSV)-2 is periodically shed in the human genital tract, most often asymptomatically. Most sexual transmissions 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. It is therefore possible to acquire the virus even if no active HSV blisters or sores are present. In one study, daily genital swab samples found HSV-2 at a median of 12–28% of days among those who have had an outbreak, and 10% of days among those suffering from asymptomatic infection, with many of these episodes occurring without visible outbreak ("subclinical shedding").
In another study, 73 subjects were randomized to receive
1 g daily or placebo for 60 days each in a 2-way . A daily swab of the genital area was self-collected for HSV-2 detection by polymerase chain reaction, in order to compare the effect of valaciclovir 1 g once daily for 60 days 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. 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. (Effect of Condoms on Reducing the Transmission of Herpes Simplex Virus Type 2 From Men to Women. A Wald, AGM Langenberg, K Link, et al. JAMA. ):3197) Atypical symptoms are often attributed to other causes such as a yeast infection. HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as
and mouth-to-genital contact (). HSV-2 is primarily a sexually transmitted infection, but rates of HSV-1 genital infections are increasing.
Both viruses may also be
during childbirth. However, the risk of infection transmission is minimal if the mother has no symptoms or exposed blisters during delivery. The risk is considerable when the mother is infected with the virus for the first time during late pregnancy.
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
which is a herpes infection on the fingers. This was a common affliction of dental surgeons prior to the routine use of gloves when conducting treatment on patients.[]
3D reconstruction and animation of a tail-like assembly on HSV-1 capsid
3D reconstruction of the Herpes simplex virus type 1 (HSV-1) capsid
Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large double-stranded, linear
encased within an
protein cage called the , which is wrapped in a
called the . The envelope is joined to the capsid by means of a . This complete particle is known as the . HSV-1 and HSV-2 each contain at least 74 genes (or , 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
of the infected host. , which encode proteins that regulate the expression of early and late viral genes, are the first to be expressed following infection.
expression follows, to allow the synthesis of
involved in
and the production of certain
. Expression of la this group of genes predominantly encode proteins that form the virion particle.
Five proteins from (UL) f , UL18, UL35, UL38 and the major capsid protein UL19.
A simplified diagram of HSV replication
Entry of HSV into a host cell involves several
on the surface of the enveloped virus binding to their
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 . 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
after binding to the receptors, and the fusion could occur at the . In electron micrographs the outer leaflets of the viral and cellular lipid bilayers h 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 particle called . 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 (), -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
on the surface of the host cell.[]
After the viral capsid enters the cellular , it is transported to the . 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, the proteins contain a
sequence of
which allow them to adhere to each other. Each
capsid contains a single portal, located in one . The DNA exits the capsid in a single linear segment.
HSV evades the immune system through interference with MHC class I
on the cell surface, by blocking TAP or the
induced by the secretion of
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.
showing the viral
of HSV (multi-nucleation, ground glass chromatin).
Following infection of a cell, a cascade of herpes virus proteins, called immediate-early, , and late, are produced. Research using
on another member of the herpes virus family, , indicates the possibility of an additional , 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- . 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 , helps in viral replication, and regulates
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 , core and the
- occurs in the nucleus of the cell. Here,
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 .
HSVs may persist in a quiescent but persistent form known as latent infection, notably in . HSV-1 tends to reside in the , while HSV-2 tends to reside in the , but these are tendencies only, not fixed behavior. During latent infection of a cell, HSVs express
(LAT) . 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 non-latency. Whether or not recurrences are symptomatic, viral shedding occurs to infect a new host. A protein found in
may bind to herpes virus DNA and regulate . Herpes virus DNA contains a gene for a protein called ICP4, which is an important
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 . When bound to the viral DNA elements,
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.
dissociates NRSF from the ICP4 gene and thus prevents silencing of the viral DNA.
The open reading frames (ORFs) of HSV-1
Function/description
Function/description
Surface and membrane
UL38; VP19C
Capsid assembly and DNA maturation
UL39; RR-1; ICP6
(Large subunit)
UL40; RR-2
Ribonucleotide reductase (Small subunit)
T Virion host shutoff
processivity factor
Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid.
Membrane protein
Virion maturation
Glycoprotein C
Surface and membrane
-associated protein
M C-type lectin
-binding protein
Tegument proteins
Glycoprotein M
Surface and membrane
UL47; VP13/14
Tegument protein
virion exit and secondary envelopment
VP16 (Alpha-TIF)
V activate
by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'.
Envelope protein
Tegument protein
Processing and packaging of DNA
DNA helicase/primase complex protein
Tegument protein
Glycoprotein K
Surface and membrane
Processing and packaging DNA
IE63; ICP27
Transcriptional regulation and inhibition of the
signalsome
Major capsid protein
Membrane protein
ICP22; IE68
Viral replication
Tegument protein
Glycoprotein H
Surface and membrane
Serine/threonine-protein kinase
Peripheral to DNA replication
Glycoprotein G
Surface and membrane
Glycoprotein J
Surface and membrane
Processing and packaging DNA
Glycoprotein D
Surface and membrane
P40; VP24; VP22A
Capsid protein
Glycoprotein I
Surface and membrane
Surface and membrane
Glycoprotein E
Surface and membrane
Processing and packaging DNA
Tegument protein
UL29; ICP8
Major DNA-binding protein
Capsid/Tegument protein
DNA replication
US11; Vmw21
Binds DNA and RNA
Nuclear matrix protein
ICP47; IE12
pathway by preventing binding of antigen to
Major transcriptional activator. Essential for progression beyond the immediate-early phase of infection.
transcription repressor.
Processing and packaging DNA
ICP0; IE110; α0
ligase that activates viral gene transcription by opposing chromatinization of the viral genome and counteracts intrinsic- and -based antiviral responses.
Inner nuclear membrane protein
Latency-related protein
Capsid protein
Latency-related protein
Large tegument protein
RL1; ICP34.5
Neurovirulence factor. Antagonizes
by de-phosphorylating eIF4a. Binds to
and inactivates .
Capsid assembly
Latency-associated transcript
ORF or feature
a sequence
Terminal direct repeat
Neurovirulence factor
Immediate- modulator of cell state and gene expression
LAT poly(A) site in circularized genome
Start of UL
Virion surface glycoprotein L
Uracil-DNA glycosylase
Nuclear phosphoprotein
Component of DNA helicase-primase
Minor capsid protein
Component of DNA helicase-primase
Ori binding protein
Virion membrane glycoprotein M
Myristylated tegument protein
P tegument protein
Role in DNA packaging
Proposed initiator CTG codon
Capsid protein
Major capsid protein (start ATG quoted is second possible)
Virion membrane protein
Tegument protein
Virion membrane glycoprotein H
Thymidine kinase (2 possible poly(A) sites)
V roles in penetration and virus assembly
Capsid maturation protease
Capsid assembly protein
Virion membrane glycoprotein B
Role in DNA packaging
Single-stranded DNA binding protein
Origin of DNA location of palindrome given
DNA polymerase catalytic subunit
Role in DNA packaging
Membrane-associated phosphoprotein
Capsid protein
Very large tegument protein (reiterations omitted for calculation of Ka and Ks)
Tegument protein
Capsid protein
Ribonucleotide reductase large subunit
Ribonucleotide reductase small subunit
T defective in HSV-2 (HG52) (see text)
DNA polymerase subunit
Probable membrane protein
Virion membrane glycoprotein C
Tegument/envelope protein
Tegument protein
Tegument protein
T transactivator of immediate-early genes
Tegument protein
Probable virion membrane protein
Deoxyuridine triphosphatase
Component of DNA helicase- ATG initiator codon quoted corresponds to HSV-1 (see text)
Membrane glycoprotein K
Immediate- posttranslational regulator of gene expression
Start of IRL
LAT initiation and poly(A) sites
Immediate- modulator of cell state and gene expression
Neurovirulence factor
a′ sequence
Opposite-sense copy of sequence directly repeated at genomic termini
Immediate- transcriptional regulator
Origin of DNA limits given are for directly repeated 138 nucleotides
Start of US
Immediate- intron in 5′ noncoding region
Protein kinase
Virion membrane glycoprotein G
Putative membrane glycoprotein J
Virion membrane glycoprotein D
Virion membrane glycoprotein I
Virion membrane glycoprotein E
Nucleolar protein
Tegument protein
Virion protein
Nucleolar, RNA binding protein
Immediate- inhibitor of
intron in 5′ noncoding region
Start of TRS
Origin of DNA limits given are for directly repeated 138 nucleotides
Immediate- transcriptional regulator
a sequence
Terminal direct repeat
The herpes simplex 1 genomes can be classified into six . Four of these occur in East Africa, one in East Asia and one in Europe and North America. This suggests that the virus may have originated in East Africa. 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.[]
Herpes simplex 2 genomes can be divided into two groups: one is globally distributed and the other is mostly limited to sub Saharan Africa. The globably distributed genotype has undergone an ancient recombination with herpes simplex 1.
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 . 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.
For more details on treatment of herpes simplex virus, see .
Herpes viruses establish lifelong infections, and the virus cannot yet be eradicated from the body. Treatment usually involves general-purpose
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 and valaciclovir can reduce reactivation rates.
It was reported, in 1979, that there is a possible link between HSV-1 and , in people with the epsilon4
of the gene . 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 , which may lead to the development of Alzheimer's disease. This research identifies HSVs as the
most clearly linked to the establishment of Alzheimer’s. According to a study done in 1997, without the presence of the gene , 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. It should be noted that 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 and P-tau, and also decreased HSV-1 replication.
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 , trimethylpsoralen (which causes inter-strand DNA cross-links), and UV light. After treatment of genetically marked HSV with trimethylpsoralen, recombination between the marked viruses increases, suggesting that trimethylpsoralen damage stimulates recombination. MR of HSV appears to partially depend on the host cell recombinational repair machinery since skin fibroblast cells defective in a component of this machinery (i.e. cells from Bloom’s syndrome patients) are deficient in MR. These observations suggest that MR in HSV infections involves genetic recombination between damaged viral genomes resulting in production of viable progeny viruses. HSV-1, upon infecting host cells, induces inflammation and oxidative stress. Thus it appears that the HSV genome may be subjected to oxidative DNA damage during infection, and that MR may enhance viral survival and virulence under these conditions.
Herpes simplex virus is considered as a potential therapy for cancer and has been extensively clinically tested to assess its
(cancer killing) ability. Interim overall survival data from 's phase 3 trial of a genetically-attenuated herpes virus suggests efficacy against melanoma.
Herpes simplex virus is also used as a transneuronal tracer defining connections among neurons by virtue of traversing synapses.
Herpes simplex virus is likely the most common cause of , and, in worse case scenarios, can lead to a potentially fatal case of .
For more details on vaccines and research milestones of herpes simplex virus, see the main article: .
There exist commonly used vaccines to some herpesviruses, but only veterinary, such as
(Turkey herpesvirus vector laryngotracheitis vaccine). However, it prevents
mirrors atherosclerosis in humans) in target animals vaccinated.
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Role of Herpesvirus in Artherogenesis edited by David P Hajjar, Stephen M Schwartz
. Public Health Agency of Canada.
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