Herpes simplex virus
Herpes simplex virus '1 and 2' are two members of the human Herpesviridae family, a set of viruses that produce viral infections in the majority of humans. Both HSV-1 and HSV-2 are very common and contagious. They can be spread when an infected person begins shedding the virus.
As of 2016, about 67% of the world population under the age of 50 had HSV-1. Because it can be transmitted through any intimate contact, it is one of the most common sexually transmitted infections.
Symptoms
Many of those who are infected never develop symptoms. Symptoms, when they occur, may include watery blisters in the skin of any location of the body, or in mucous membranes of the mouth, lips, nose, genitals, or eyes. 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, 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 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, with many of these episodes occurring without visible outbreak.
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.
For HSV-2, subclinical shedding may account for most of the transmission. Studies on discordant partners show that the transmission rate is approximately 5–8.9 per 10,000 sexual contacts, with condom usage greatly reducing the risk of acquisition. 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 kissing and oral sex. 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 natural 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 a high viral load.
Herpes simplex virus is highly unstable outside the human body. Although short-term survival on surfaces has been demonstrated under laboratory conditions, the virus rapidly loses infectivity once exposed to air. Consequently, transmission via inanimate objects such as towels or toilet seats is generally considered extremely unlikely. HSV transmission occurs primarily through direct contact with infected skin or mucosa, not through shared objects.
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; it was commonly found on dental surgeon's hands before the routine use of gloves when treating patients. Shaking hands with an infected person does not transmit this disease. Genital infection of HSV-2 increases the risk of acquiring HIV.
Virology
HSV has been a model virus for many studies in molecular biology. For instance, one of the first functional promoters in eukaryotes was discovered in HSV and the virion protein VP16 is one of the most-studied transcriptional activators.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 through a tegument. This complete particle is known as the virion. HSV-1 and HSV-2 each contain at least 74 genes 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 and the short unique region. 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 of the infected host. Immediate early genes, 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 enzymes involved in DNA replication and the production of certain envelope glycoproteins. Expression of late genes occurs last; this group of genes predominantly encodes proteins that form the virion particle.
Five proteins from 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 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. 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; 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 glycoproteins called glycoprotein C and glycoprotein B bind to a cell surface polysaccharide called heparan sulfate. Next, the major receptor binding protein, glycoprotein D, binds specifically to at least one of three known entry receptors. These cell receptors include herpesvirus entry mediator, 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. 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 and L, 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 glycosaminoglycans on the surface of the host cell.
Genetic inoculation
After the viral capsid enters the cellular cytoplasm, it starts to express viral protein . ICP27 is a regulator protein that causes disruption in host protein synthesis and utilizes it for viral replication. ICP27 binds with a cellular enzyme Serine-Arginine Protein Kinase 1, SRPK1. Formation of this complex causes the SRPK1 shift from the cytoplasm to the nucleus, and the viral genome gets 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 the 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. Each icosahedral capsid contains a single portal, located in one vertex.The DNA exits the capsid in a single linear segment.