Herpes simplex virus

This article is about the virus. For information about the disease caused by the virus, see Herpes simplex.
Herpes simplex virus
TEM micrograph of a herpes simplex virus
Virus classification
Group: Group I (dsDNA)
Order: Herpesvirales
Family: Herpesviridae
Subfamily: Alphaherpesvirinae
Genus: Simplexvirus
Species
  • Herpes simplex virus 1 (HSV-1)
  • Herpes simplex virus 2 (HSV-2)

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, Herpesviridae, that infect humans.[1] Both HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious. They can be spread when an infected person is producing and shedding the virus. Herpes simplex can be spread through contact with saliva, such as sharing drinks.

Symptoms of herpes simplex virus infection include watery blisters in the skin or mucous membranes of the mouth, lips or genitals.[1] Lesions heal with a scab characteristic of herpetic disease. Sometimes, the viruses cause very mild or atypical symptoms during outbreaks. However, as neurotropic and neuroinvasive viruses, HSV-1 and -2 persist in the body by becoming latent and hiding from the immune system in the cell bodies of 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.[2] It is one of the most common sexually transmitted infections.[3]

Transmission

Main article: Herpes simplex

HSV-1 and -2 are transmitted by contact with an infected area of the skin during reactivations of the virus. Herpes simplex virus (HSV)-2 is periodically shed in the human genital tract, most often asymptomatically, and most sexual transmissions occur during asymptomatic shedding.[4] Asymptomatic reactivation means that the virus causes atypical, subtle or hard to notice symptoms that are not identified as an active herpes infection. 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").[5]

In another study, seventy-three subjects were randomized to receive valaciclovir 1 g daily or placebo for 60 days each in a 2-way crossover design. 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.[6]

For HSV-2, subclinical shedding may account for most of the transmission, and one study found that infection occurred after a median of 40 sex acts.[5] Atypical symptoms are often attributed to other causes such as a yeast infection.[7][8] 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).[9] HSV-2 is primarily a sexually transmitted infection, but rates of HSV-1 genital infections are increasing.[7]

Both viruses may also be transmitted vertically during childbirth, although the real risk is very low.[10] The risk of infection 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.[11]

Herpes simplex viruses can affect areas of skin exposed to contact with an infected person. 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.

Microbiology

Viral structure

3D reconstruction and animation of a tail-like assembly in HSV-1 virion
3D reconstruction of Herpes simplex virus type 1 (HSV-1)

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.[12] HSV-1 and HSV-2 each contain at least 74 genes (or open reading frames, ORFs) within their genomes,[13] although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.[14] 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.[13] Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host.[13] 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.[13]

Five proteins from (UL) form the viral capsid; UL6, UL18, UL35, UL38 and the major capsid protein UL19.[12]

Cellular entry

A simplified diagram of HSV replication

Entry of HSV into the host cell involves interactions of several glycoproteins on the surface of the enveloped virus, with receptors on the surface of the host cell. The envelope covering the virus particle, when bound to specific receptors on the cell surface, will fuse with the host cell membrane and create an opening, or pore, through which the virus enters the host cell.

The sequential stages of HSV entry are analogous to those of other viruses. At first, complementary receptors on the virus and the cell surface bring the viral and cell membranes into proximity. In an intermediate state, the two membranes begin to merge, forming a hemifusion state. Finally, a stable entry pore is formed through which the viral envelope contents are introduced to the host cell.[15] The virus can also be endocytosed after binding to the receptors, and the fusion could occur at the endosome.

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.[16] These include herpesvirus entry mediator (HVEM), nectin-1 and 3-O sulfated heparan sulfate. The receptor provides a strong, fixed attachment to the host cell. These interactions bring the membrane surfaces into mutual proximity and allow for other glycoproteins embedded in the viral envelope to interact with other cell surface molecules. Once bound to the HVEM, gD changes its conformation and interacts with viral glycoproteins H (gH) and L (gL), which form a complex. The interaction of these membrane proteins results in the hemifusion state. Afterward, gB interaction with the gH/gL complex creates an entry pore for the viral capsid.[15] gB interacts with glycosaminoglycans on the surface of the host cell.

Genetic inoculation

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 twelve copies of portal protein, UL6, arranged as a ring; the proteins contain a leucine zipper sequence of amino acids which allow them to adhere to each other.[17] Each icosahedral capsid contains a single portal, located in one vertex.[18][19] The DNA exits the capsid in a single linear segment.[20]

Immune evasion

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.[21] In the host cell, TAP transports digested viral antigen epitopes 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.

Replication

Micrograph showing the viral cytopathic effect of HSV (multi-nucleation, ground glass chromatin).

Following infection of a cell, a cascade of herpes virus proteins, called immediate-early, early, and late, are produced. Research using flow cytometry on another member of the herpes virus family, Kaposi's sarcoma-associated herpesvirus, indicates the possibility of an additional lytic stage, delayed-late.[22] 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.[23] 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.[24][25]

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 pre-formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. The primary envelope is acquired by budding into the inner nuclear membrane of the cell. This then fuses with the outer nuclear membrane releasing a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into cytoplasmic vesicles.[26]

Latent infection

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 non-latency. 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.[27] 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.[27][28] 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.[29]

The virus can be reactivated by illnesses such as colds and influenza, eczema, emotional and physical stress, gastric upset, fatigue or injury, by menstruation and possibly exposure to bright sunlight. Genital Herpes may be reactivated by friction.

Viral genome

The open reading frames (ORFs) of HSV-1[13][30]
Gene Protein Function/description Gene Protein Function/description
UL1 Glycoprotein L Surface and membrane UL38 UL38; VP19C Capsid assembly and DNA maturation
UL2 UL2 Uracil-DNA glycosylase UL39 UL39 Ribonucleotide reductase (Large subunit)
UL3 UL3 unknown UL40 UL40 Ribonucleotide reductase (Small subunit)
UL4 UL4 unknown UL41 UL41; VHS Tegument protein; Virion host shutoff[23]
UL5 UL5 DNA replication UL42 UL42 DNA polymerase processivity factor
UL6 Portal protein UL-6 Twelve of these proteins constitute the capsid portal ring through which DNA enters and exits the capsid.[17][18][19] UL43 UL43 Membrane protein
UL7 UL7 Virion maturation UL44 Glycoprotein C Surface and membrane
UL8 UL8 DNA helicase/primase complex-associated protein UL45 UL45 Membrane protein; C-type lectin[31]
UL9 UL9 Replication origin-binding protein UL46 VP11/12 Tegument proteins
UL10 Glycoprotein M Surface and membrane UL47 UL47; VP13/14 Tegument protein
UL11 UL11 virion exit and secondary envelopment UL48 VP16 (Alpha-TIF) Virion maturation; activate IE genes by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'.
UL12 UL12 Alkaline exonuclease UL49 UL49A Envelope protein
UL13 UL13 Serine-threonine protein kinase UL50 UL50 dUTP diphosphatase
UL14 UL14 Tegument protein UL51 UL51 Tegument protein
UL15 Terminase Processing and packaging of DNA UL52 UL52 DNA helicase/primase complex protein
UL16 UL16 Tegument protein UL53 Glycoprotein K Surface and membrane
UL17 UL17 Processing and packaging DNA UL54 IE63; ICP27 Transcriptional regulation
UL18 VP23 Capsid protein UL55 UL55 Unknown
UL19 VP5 Major capsid protein UL56 UL56 Unknown
UL20 UL20 Membrane protein US1 ICP22; IE68 Viral replication
UL21 UL21 Tegument protein[32] US2 US2 Unknown
UL22 Glycoprotein H Surface and membrane US3 US3 Serine/threonine-protein kinase
UL23 Thymidine kinase Peripheral to DNA replication US4 Glycoprotein G Surface and membrane
UL24 UL24 unknown US5 Glycoprotein J Surface and membrane
UL25 UL25 Processing and packaging DNA US6 Glycoprotein D Surface and membrane
UL26 P40; VP24; VP22A Capsid protein US7 Glycoprotein I Surface and membrane
UL27 Glycoprotein B Surface and membrane US8 Glycoprotein E Surface and membrane
UL28 ICP18.5 Processing and packaging DNA US9 US9 Tegument protein
UL29 UL29; ICP8 Major DNA-binding protein US10 US10 Capsid/Tegument protein
UL30 DNA polymerase DNA replication US11 US11; Vmw21 Binds DNA and RNA
UL31 UL31 Nuclear matrix protein US12 ICP47; IE12 Inhibits MHC class I pathway by preventing binding of antigen to TAP
UL32 UL32 Envelope glycoprotein RS1 ICP4; IE175 Major transcriptional activator. Essential for progression beyond the immediate-early phase of infection. IEG transcription repressor.
UL33 UL33 Processing and packaging DNA ICP0 ICP0; IE110; α0 E3 ubiquitin ligase that activates viral gene transcription by opposing chromatinization of the viral genome and counteracts intrinsic- and interferon-based antiviral responses.[33]
UL34 UL34 Inner nuclear membrane protein LRP1 LRP1 Latency-related protein
UL35 VP26 Capsid protein LRP2 LRP2 Latency-related protein
UL36 UL36 Large tegument protein RL1 RL1; ICP34.5 Neurovirulence factor. Antagonizes PKR by de-phosphorylating eIF4a. Binds to BECN1 and inactivates autophagy.
UL37 UL37 Capsid assembly LAT none Latency-associated transcript

Evolution

The herpes simplex 1 genomes can be classified into six clades.[34] 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.[35] 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.

The mutation rate has been estimated to be ~1.38×10−7 substitutions/site/year.[34] 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.[36]

Treatment and vaccine development

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

Herpes viruses establish lifelong infections, and the virus cannot yet be eradicated from the body. 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[37] and valaciclovir can reduce reactivation rates.[8]

Alzheimer's disease

In the presence of a certain gene variation (APOE-epsilon4 allele carriers), a possible link between HSV-1 (i.e., the virus that causes cold sores or oral herpes) and Alzheimer's disease was reported in 1979.[38] 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.[39] This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s.[40] 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.[41] 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.[42] 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.[43]

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.[44]

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,[45] trimethylpsoralen (which causes inter-strand DNA cross-links),[46][47] and UV light.[48] After treatment of genetically marked HSV with trimethylpsoralen, recombination between the marked viruses increases, suggesting that trimethylpsoralen damages stimulate recombination.[46] 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.[48] 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.[49] 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

Herpes simplex virus is considered as a potential therapy for cancer and has been extensively clinically tested to assess its oncolytic (cancer killing) ability.[50] Interim overall survival data from Amgen's phase 3 trial of a genetically-attenuated herpes virus suggests efficacy against melanoma.[51]

Use in neuronal connection tracing

Herpes simplex virus is also used as a transneuronal tracer defining connections among neurons by virtue of traversing synapses.[52]

References

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