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Herpes simplex virus

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This article is about the virus. For information about the disease caused by the virus, see Herpes simplex.

Herpes simplex virus
File:Herpes simpex virus.jpg
TEM micrograph of a herpes simplex virus.
Virus classification
Group:
Group I (dsDNA)
Family:
Herpesviridae
Subfamily:
Alphaherpesvirinae
Genus:
Simplexvirus
Species

Herpes simplex virus 1 (HWJ-1)
Herpes simplex virus 2 (HWJ-2)

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two species of the herpes virus family, Herpesviridae, which cause infections in humans.[1] As with other herpesviridae, herpes simplex virus may produce life-long infections.

They are also called Human Herpes Virus 1 and 2 (HHV-1 and HHV-2) and are neurotropic and neuroinvasive viruses; they enter and hide in the human nervous system, accounting for their durability in the human body. HSV-1 is commonly associated with herpes outbreaks of the face known as cold sores or fever blisters, whereas HSV-2 is more often associated with genital herpes.

An infection by a herpes simplex virus is marked by watery blisters in the skin or mucous membranes of the mouth, lips or genitals.[1] Lesions heal with a scab characteristic of herpetic disease. However, the infection is persistent and symptoms may recur periodically as outbreaks of sores near the site of original infection. After the initial, or primary, infection, HSV becomes latent in the cell bodies of nerves in the area. Some infected people experience sporadic episodes of viral reactivation, followed by transportation of the virus via the nerve's axon to the skin, where virus replication and shedding occurs.[2]

Herpes is contagious if the carrier is producing and shedding the virus. This is especially likely during an outbreak but possible at other times. There is no cure yet, but there are treatments which reduce the likelihood of viral shedding. Aloe Vera was researched as being effective against genital herpes. [3][4] Also, one species of Euphorbiaceae proved effective against genital herpes (HSV-2). [5]

Transmission

Main article: Herpes simplex

HSV is transmitted during close contact with an infected person who is shedding virus from the skin, in saliva or in secretions from the genitals. This horizontal transmission of the virus is more likely to occur when sores are present, although viral shedding, and therefore transmission, does occur in the absence of visible sores.[6] In addition, vertical transmission of HSV may occur between mother and child during childbirth, which can be fatal to the infant.[7] The immature immune system of the child is unable to defend against the virus and even if treated, the infection can result in inflammation of the brain (encephalitis) that may cause brain damage. Transmission occurs when the infant passes through the birth canal, but the risk of infection is reduced if there are no symptoms or exposed blisters during delivery. The first outbreak after exposure to HSV is commonly more severe than future outbreaks, as the body has not had a chance to produce antibodies; this first outbreak carries a low (≈1%) risk of developing aseptic meningitis.[1].

Microbiology

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 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.[8] HSV-1 and HSV-2 each contain at least 74 genes (or open-reading frames, ORFs) within their genomes,[9] although speculation over gene crowding allows as many as 84 unique protein coding genes by 94 putative ORFs.[10] 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.[9] Transcription of HSV genes is catalyzed by RNA polymerase II of the infected host.[9] 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.[9]

Five proteins from (UL) form the viral capsid; UL6, UL18, UL35, UL38 and the major capsid protein UL19.[8]

The open reading frames (ORFs) of HSV-1[9][11]
Gene Protein Function/description Gene Protein Function/description
UL1 Glycoprotein L [1] Surface and membrane UL38 UL38; VP19C [2] Capsid assembly and DNA maturation
UL2 UL2 [3] Uracil-DNA glycosylase UL39 UL39 [4] Ribonucleotide reductase (Large subunit)
UL3 UL3 [5] unknown UL40 UL40 [6] Ribonucleotide reductase (Small subunit)
UL4 UL4 [7] unknown UL41 UL41; VHS [8] Tegument protein; Virion host shutoff[12]
UL5 UL5 [9] DNA replication UL42 UL42 [10] DNA polymerase processivity factor
UL6 UL6 [11] Processing and packaging DNA UL43 UL43 [12] Membrane protein
UL7 UL7 [13] Virion maturation UL44 Glycoprotein C [14] Surface and membrane
UL8 UL8 [15] DNA helicase/primase complex-associated protein UL45 UL45 [16] Membrane protein; C-type lectin[13]
UL9 UL9 [17] Replication origin-binding protein UL46 VP11/12 [18] Tegument proteins
UL10 Glycoprotein M [19] Surface and membrane UL47 UL47; VP13/14 [20] Tegument protein
UL11 UL11 [21] virion exit and secondary envelopment UL48 VP16 (Alpha-TIF) [22] Virion maturation; activate IEGs by interacting with the cellular transcription factors Oct-1 and HCF. Binds to the sequence 5'TAATGARAT3'.
UL12 UL12 [23] Alkaline exonuclease UL49 UL49A [24] Envelope protein
UL13 UL13 [25] Serine-threonine protein kinase UL50 UL50 [26] dUTP diphosphatase
UL14 UL14 [27] Tegument protein UL51 UL51 [28] Tegument protein
UL15 Terminase [29] Processing and packaging of DNA UL52 UL52 [30] DNA helicase/primase complex protein
UL16 UL16 [31] Tegument protein UL53 Glycoprotein K [32] Surface and membrane
UL17 UL17 [33] Processing and packaging DNA UL54 IE63; ICP27 [34] Transcriptional regulation
UL18 VP23 [35] Capsid protein UL55 UL55 [36] Unknown
UL19 VP5 [37] Major capsid protein UL56 UL56 [38] Unknown
UL20 UL20 [39] Membrane protein US1 ICP22; IE68 [40] Viral replication
UL21 UL21 [41] Tegument protein[14] US2 US2 [42] Unknown
UL22 Glycoprotein H [43] Surface and membrane US3 US3 [44] Serine/threonine-protein kinase
UL23 Thymidine kinase [45] Peripheral to DNA replication US4 Glycoprotein G [46] Surface and membrane
UL24 UL24 [47] unknown US5 Glycoprotein J [48] Surface and membrane
UL25 UL25 [49] Processing and packaging DNA US6 Glycoprotein D [50] Surface and membrane
UL26 P40; VP24; VP22A [51] Capsid protein US7 Glycoprotein I [52] Surface and membrane
UL27 Glycoprotein B [53] Surface and membrane US8 Glycoprotein E [54] Surface and membrane
UL28 ICP18.5 [55] Processing and packaging DNA US9 US9 [56] Tegument protein
UL29 UL29 [57] Major DNA-binding protein US10 US10 [58] Capsid/Tegument protein
UL30 DNA polymerase [59] DNA replication US11 US11; Vmw21 [60] Binds DNA and RNA
UL31 UL31 [61] Nuclear matrix protein US12 ICP47; IE12 [62] Inhibits MHC class I pathway by preventing binding of antigen to TAP
UL32 UL32 [63] Envelope glycoprotein RS1 ICP4; IE175 [64] Activates gene transcription
UL33 UL33 [65] Processing and packaging DNA ICP0 ICP0; IE110; α0 [66] E3 ubiquitin ligase that activates viral gene transcription and counteracts the interferon response
UL34 UL34 [67] Inner nuclear membrane protein LRP1 LRP1 [68] Latency-related protein
UL35 VP26 [69] Capsid protein LRP2 LRP2 [70] Latency-related protein
UL36 UL36 [71] Large tegument protein RL1 RL1; ICP34.5 [72] Neurovirulence factor. Antagonizes PKR by de-phosphorylating eIF4a.
UL37 UL37 [73] Capsid assembly LAT none [74] Latency-associated transcript

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] In the case of a herpes virus, initial interactions occur when a viral envelope glycoprotein called glycoprotein C (gC) binds to a cell surface particle called heparan sulfate. A second glycoprotein, glycoprotein D (gD), binds specifically to a receptor called the herpesvirus entry mediator receptor (HVEM) and 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] Glycoprotein B 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.[16] Each icosahedral capsid contains a single portal, located in one vertex.[17][18] The DNA exits the capsid in a single linear segment.[19]

Replication

Following infection of a cell, herpes virus proteins, called immediate-early, early, and late, are produced. Research using flow cytometry on another member of the herpes virus family, KSHV, indicates the possibility of an additional lytic stage, delayed-late.[20] 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.[12] 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.[21][22]

The late proteins are used in to form the capsid and the receptors on the surface of the virus. Packaging of the viral particles — including the genome, core and the capsid - occurs in the nucleus of the cell. Here, concatemers of the viral genome are separated by cleavage and are placed into pre-formed capsids. HSV-1 undergoes a process of primary and secondary envelopment. The primary envelope is acquired by budding into the inner nuclear membrane of the cell. This then fuses with the outer nuclear membrane releasing a naked capsid into the cytoplasm. The virus acquires its final envelope by budding into cytoplasmic vesicles.[23]

Latent infection

HSV may persist in a quiescent but persistent form known as latent infection, notably in neural ganglia.[1] During latent infection of a cell, HSV express Latency Associated Transcript (LAT) RNA. LAT is known to regulate the host cell genome and interferes with natural cell death mechanisms. By maintaining the host cells, LAT expression preserves a reservoir of the virus, which allows later recurrences to produce further infections.

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.[24] 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 deacytalization 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.[25][26] 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.[27]

The virus can be reactivated by other illnesses such as cold and influenza, eczema, emotional and physical stress, exposure to bright sunlight, gastric upset, fatigue or injury, and by menstruation.

Treatment

Herpes viruses are known for their ability to establish lifelong, incurable infections. Treatment usually involves general-purpose antiviral drugs which reduce the infection, but are unable to completely eliminate it. The antiviral most commonly used is Aciclovir or Acyclovir. Reducing the viral load can reduce the physical severity of outbreak-associated lesions and the amount of infected cells shed by the body, lowering the chance of transmission to others. Research has also shown that the virus's growth is to a moderate degree proportional to the ratio of the amino acid arginine to the amino acid lysine in the diet of infected individuals.[28] Whilst this applies to viral growth in the laboratory, the Herpes Viruses Association recommends that patients who are considering adjusting their diet first test their susceptibility to the lysine/arginine balance in their bodies: avoiding arginine-rich foods for a period of time, then indulging in these foods (chocolate and nuts are prime candidates) to see if an outbreak is then triggered.

Research into a vaccine is ongoing.

Further information: Herpes labialis § Treatment

Alzheimer's disease

Scientists discovered a link between HSV-1 and Alzheimer’s disease in 1979.[29] In the presence of a certain gene variation (APOE-epsilon4 allele carriers), 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.[30] This research identifies HSVs as the pathogen most clearly linked to the establishment of Alzheimer’s.[31] Without the presence of the gene allele, HSV type 1 does not appear to cause any neurological damage and thus increase the risk of Alzheimer’s.[32]

A 2008 study published in The Journal of Pathology, [33] has shown a striking localization of herpes simplex virus type 1 DNA within the beta-amyloid plaques that characterize Alzheimer's disease, and suggests that this virus is a major cause of the plaques and hence probably a significant aetiological factor in Alzheimer's disease.

References

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  24. ^ Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC (2007). "Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification". Virol. J. 4: 56. doi:10.1186/1743-422X-4-56. PMID 17555596.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  25. ^ Pinnoji RC, Bedadala GR, George B, Holland TC, Hill JM, Hsia SC (2007). "Repressor element-1 silencing transcription factor/neuronal restrictive silencer factor (REST/NRSF) can regulate HSV-1 immediate-early transcription via histone modification". Virol. J. 4: 56. doi:10.1186/1743-422X-4-56. PMID 17555596.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
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  31. ^ Pyles RB (2001). "The association of herpes simplex virus and Alzheimer's disease: a potential synthesis of genetic and environmental factors" (PDF). Herpes. 8 (3): 64–8. PMID 11867022. {{cite journal}}: Unknown parameter |month= ignored (help)
  32. ^ Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997). "Herpes simplex virus type 1 in brain and risk of Alzheimer's disease". Lancet. 349 (9047): 241–4. doi:10.1016/S0140-6736(96)10149-5. PMID 9014911. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  33. ^ Wozniak MA, Mee AP, Itzhaki RF (2009). "Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques". J. Pathol. 217 (1): 131–8. doi:10.1002/path.2449. PMID 18973185. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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