Herpes simplex virus

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Herpes simplex viruses
TEM micrograph of virions of a herpes simplex virus species
TEM micrograph of virions of a herpes simplex virus species
Scientific classificationEdit this classification
(unranked): Virus
Phylum: incertae sedis
Class: incertae sedis
Order: Herpesvirales
Family: Herpesviridae
Subfamily: Alphaherpesvirinae
Genus: Simplexvirus
Groups included
Cladistically included but traditionally excluded taxa

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names Human alphaherpesvirus 1 and Human alphaherpesvirus 2, are two members of the human Herpesviridae family, a set of viruses that produce viral infections in the majority of humans.[1][2] Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are common and contagious. They can be spread when an infected person begins shedding the virus. About 67% of the world population under the age of 50 has HSV-1.[3] In the United States more than one in six people have HSV-2.[4] Although it can be transmitted through any intimate contact, it is one of the most common sexually transmitted infections.[5]

Many of those who are infected never develop symptoms.[6] Symptoms, when they occur, may include watery blisters in the skin or mucous membranes of the mouth, lips, nose, or genitals.[1] 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. As neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by hiding from the immune system in the cell bodies of neurons. 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 to the skin, where virus replication and shedding occur and cause new sores.[7]

Transmission[edit]

HSV-1 and HSV-2 are transmitted by contact with an infected person who has reactivations of the virus. HSV-2 is periodically shed in the human genital tract, most often asymptomatically. Most sexual transmissions occur during periods of asymptomatic shedding.[8] 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 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").[9]

In another study, 73 subjects were randomized to receive valaciclovir 1 g daily or placebo for 60 days each in a two-way crossover design. 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.[10]

For HSV-2, subclinical shedding may account for most of the transmission.[9] Studies on discordant partners (one infected with HSV-2, one not) show that the transmission rate is approximately 5 per 10,000 sexual contacts.[11] Atypical symptoms are often attributed to other causes, such as a yeast infection.[12][13] HSV-1 is often acquired orally during childhood. It may also be sexually transmitted, including contact with saliva, such as kissing and mouth-to-genital contact (oral sex).[14] HSV-2 is primarily a sexually transmitted infection, but rates of HSV-1 genital infections are increasing.[12]

Both viruses may also be transmitted vertically during childbirth.[15] 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.[16] Contrary to popular myths, herpes cannot be transmitted from surfaces such as toilet seats because the herpes virus begins to die immediately after leaving the body. [17]

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, 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.[citation needed]

Virology[edit]

Viral structure[edit]

A three-dimensional reconstruction and animation of a tail-like assembly on HSV-1 capsid
3D reconstruction of the HSV-1 capsid

Animal herpes viruses all share some common properties. The structure of herpes viruses consists of a relatively large, double-stranded, linear DNA 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.[18] HSV-1 and HSV-2 each contain at least 74 genes (or open reading frames, ORFs) within their genomes,[19] although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.[20] 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.[19] Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host.[19] Immediate early genes, 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 enzymes involved in DNA replication and the production of certain envelope glycoproteins. Expression of late genes occurs last; this group of genes predominantly encode proteins that form the virion particle.[19]

Five proteins from (UL) form the viral capsid - UL6, UL18, UL35, UL38, and the major capsid protein UL19.[18]

Cellular entry[edit]

A simplified diagram of HSV replication

Entry of HSV into a host cell involves several glycoproteins on the surface of the enveloped virus binding to their transmembrane receptors 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.[21] 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. In electron micrographs, the outer leaflets of the viral and cellular lipid bilayers have been seen merged;[22] 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 heparan sulfate. Next, the major receptor binding protein, glycoprotein D (gD), binds specifically to at least one of three known entry receptors.[23] These cell receptors include herpesvirus entry mediator (HVEM), nectin-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.[21] 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.[22] gB interacts with glycosaminoglycans on the surface of the host cell.[citation needed]

Genetic inoculation[edit]

After the viral capsid enters the cellular cytoplasm, 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 12 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.[24] Each icosahedral capsid contains a single portal, located in one vertex.[25][26] The DNA exits the capsid in a single linear segment.[27]

Immune evasion[edit]

HSV evades the immune system through interference with MHC class I antigen presentation on the cell surface, by blocking the transporter associated with antigen processing (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.[28]

Replication[edit]

Micrograph showing the viral cytopathic effect of HSV (multinucleation, ground glass chromatin)

Following infection of a cell, a cascade of herpes virus proteins, called immediate-early, early, and late, is 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.[29] 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.[30] 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.[31][32]

The late proteins 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 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.[33]

Latent infection[edit]

HSVs may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia.[1] HSV-1 tends to reside in the trigeminal ganglia, while HSV-2 tends to reside in the sacral ganglia, but these are tendencies only, not fixed behavior. During latent infection of a cell, HSVs express latency-associated transcript (LAT) RNA. 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 of genes associated with lytic infection in HSV-1.[34] 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.[34][35] 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.[36]

Genome[edit]

The HSV genome 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 nearthe RS.[37] 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.[38]

The open reading frames (ORFs) of HSV[19][39]
ORF Protein alias HSV-1 HSV-2 Function/description
Repeat long (RL)
ICP0/RL2 ICP0; IE110; α0 P08393 P28284 E3 ubiquitin ligase that activates viral gene transcription by opposing chromatinization of the viral genome and counteracts intrinsic- and interferon-based antiviral responses.[40]
RL1 RL1; ICP34.5 O12396 Neurovirulence factor. Antagonizes PKR by de-phosphorylating eIF4a. Binds to BECN1 and inactivates autophagy.
LAT LRP1, LRP2 P17588
P17589
Latency-associated transcript abd protein products (latency-related protein)
Unique long (UL)
UL1 Glycoprotein L P10185 Surface and membrane
UL2 UL2 P10186 Uracil-DNA glycosylase
UL3 UL3 P10187 unknown
UL4 UL4 P10188 unknown
UL5 UL5 Q2MGV2 DNA replication
UL6 Portal protein UL-6 P10190 Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid.[24][25][26]
UL7 UL7 P10191 Virion maturation
UL8 UL8 P10192 DNA virus helicase-primase complex-associated protein
UL9 UL9 P10193 Replication origin-binding protein
UL10 Glycoprotein M P04288 Surface and membrane
UL11 UL11 P04289 virion exit and secondary envelopment
UL12 UL12 Q68978 Alkaline exonuclease
UL13 UL13 Q9QNF2 Serine-threonine protein kinase
UL14 UL14 P04291 Tegument protein
UL15 Terminase P04295 Processing and packaging of DNA
UL16 UL16 P10200 Tegument protein
UL17 UL17 P10201 Processing and packaging DNA
UL18 VP23 P10202 Capsid protein
UL19 VP5 P06491 Major capsid protein
UL20 UL20 P10204 Membrane protein
UL21 UL21 P10205 Tegument protein[41]
UL22 Glycoprotein H P06477 Surface and membrane
UL23 Thymidine kinase O55259 Peripheral to DNA replication
UL24 UL24 P10208 unknown
UL25 UL25 P10209 Processing and packaging DNA
UL26 P40; VP24; VP22A; UL26.5 (HHV2 short isoform) P10210 P89449 Capsid protein
UL27 Glycoprotein B A1Z0P5 Surface and membrane
UL28 ICP18.5 P10212 Processing and packaging DNA
UL29 UL29; ICP8 Q2MGU6 Major DNA-binding protein
UL30 DNA polymerase Q4ACM2 DNA replication
UL31 UL31 Q25BX0 Nuclear matrix protein
UL32 UL32 P10216 Envelope glycoprotein
UL33 UL33 P10217 Processing and packaging DNA
UL34 UL34 P10218 Inner nuclear membrane protein
UL35 VP26 P10219 Capsid protein
UL36 UL36 P10220 Large tegument protein
UL37 UL37 P10216 Capsid assembly
UL38 UL38; VP19C P32888 Capsid assembly and DNA maturation
UL39 UL39; RR-1; ICP6 P08543 Ribonucleotide reductase (large subunit)
UL40 UL40; RR-2 P06474 Ribonucleotide reductase (small subunit)
UL41 UL41; VHS P10225 Tegument protein; virion host shutoff[30]
UL42 UL42 Q4H1G9 DNA polymerase processivity factor
UL43 UL43 P10227 Membrane protein
UL44 Glycoprotein C P10228 Surface and membrane
UL45 UL45 P10229 Membrane protein; C-type lectin[42]
UL46 VP11/12 P08314 Tegument proteins
UL47 UL47; VP13/14 P10231 Tegument protein
UL48 VP16 (Alpha-TIF) P04486 Virion maturation; activate IE genes by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'.
UL49 UL49A O09800 Envelope protein
UL50 UL50 P10234 dUTP diphosphatase
UL51 UL51 P10234 Tegument protein
UL52 UL52 P10236 DNA helicase/primase complex protein
UL53 Glycoprotein K P68333 Surface and membrane
UL54 IE63; ICP27 P10238 Transcriptional regulation and inhibition of the STING signalsome[43]
UL55 UL55 P10239 Unknown
UL56 UL56 P10240 Unknown
Inverted repeat long (IRL)
Inverted repeat short (IRS)
Unique short (US)
US1 ICP22; IE68 P04485 Viral replication
US2 US2 P06485 Unknown
US3 US3 P04413 Serine/threonine-protein kinase
US4 Glycoprotein G P06484 Surface and membrane
US5 Glycoprotein J P06480 Surface and membrane
US6 Glycoprotein D A1Z0Q5 Surface and membrane
US7 Glycoprotein I P06487 Surface and membrane
US8 Glycoprotein E Q703F0 Surface and membrane
US9 US9 P06481 Tegument protein
US10 US10 P06486 Capsid/Tegument protein
US11 US11; Vmw21 P56958 Binds DNA and RNA
US12 ICP47; IE12 P03170 Inhibits MHC class I pathway by preventing binding of antigen to TAP
Terminal repeat short (TRS)
RS1 ICP4; IE175 P08392 Major transcriptional activator. Essential for progression beyond the immediate-early phase of infection. IEG transcription repressor.

Evolution[edit]

The herpes simplex 1 genomes can be classified into six clades.[44] 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 most recent common ancestor of the Eurasian strains appears to have evolved ~60,000 years ago.[45] 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.[citation needed]

Herpes simplex 2 genomes can be divided into two groups: one is globally distributed and the other is mostly limited to sub Saharan Africa.[46] The globably distributed genotype 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.[47]

The mutation rate has been estimated to be ~1.38×10−7 substitutions/site/year.[44] In clinical setting, the mutations in either the thymidine kinase gene or DNA polymerase gene has caused resistance to aciclovir. However, most of the mutations occur in the thymidine kinase gene rather than the DNA polymerase gene.[48]

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.[49]

Herpes simplex 1 and 2 diverged about 6 million years ago.[47]

Treatment[edit]

For more details on treatment of herpes simplex virus, see Herpes simplex.

The herpes viruses establish lifelong infections (thus cannot be eradicated from the body).[50] Because the virus is a foreign pathogen, a human body's immune system as well as its specialty antigen naturally diminishes the virus.[50]

Treatment usually involves general-purpose antiviral drugs 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[51] and valaciclovir can reduce reactivation rates.[13]

Alzheimer's disease[edit]

It was reported, in 1979, that there is a possible link between HSV-1 and Alzheimer's disease, in people with the epsilon4 allele of the gene APOE.[52] 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.[53] This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s.[54] According to a study done in 1997, without the presence of the gene allele, HSV-1 does not appear to cause any neurological damage or increase the risk of Alzheimer’s.[55] 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.[56] 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 tau protein, and also decreased HSV-1 replication.[57]

A 2018 retrospective study from Taiwan 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, famciclovir, ganciclovir, idoxuridine, penciclovir, tromantadine, valaciclovir, or valganciclovir) showed no elevated risk of dementia compared to patients uninfected with HSV.[58]

Multiplicity reactivation[edit]

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.[59]

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,[60] trimethylpsoralen (which causes inter-strand DNA cross-links),[61][62] and UV light.[63] After treatment of genetically marked HSV with trimethylpsoralen, recombination between the marked viruses increases, suggesting that trimethylpsoralen damage stimulates recombination.[61] 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.[63] 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.[64] 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.

Use as an anti-cancer agent[edit]

Modified Herpes simplex virus is considered as a potential therapy for cancer and has been extensively clinically tested to assess its oncolytic (cancer killing) ability.[65] Interim overall survival data from Amgen's phase 3 trial of a genetically-attenuated herpes virus suggests efficacy against melanoma.[66]

Use in neuronal connection tracing[edit]

Herpes simplex virus is also used as a transneuronal tracer defining connections among neurons by virtue of traversing synapses.[67]

Other related outcomes[edit]

Herpes simplex virus is likely the most common cause of Mollaret's meningitis.[68] In worst-case scenarios, it can lead to a potentially fatal case of herpes simplex encephalitis.[69]

Research[edit]

For more details on vaccines and research milestones of herpes simplex virus, see the main article: Herpes simplex research.

There exist commonly used vaccines to some herpesviruses, but only veterinary, such as HVT/LT (Turkey herpesvirus vector laryngotracheitis vaccine). However, it prevents atherosclerosis (which histologically mirrors atherosclerosis in humans) in target animals vaccinated.[70][71]

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