The virus exhibits three different latency programs, each comprising a limited and distinct set of viral proteins and RNAs 32 , Upon infecting a resting B-cell, the virus starts with the more comprehensive latency III program. The resulting proteins induce the B-cell to proliferate.
The virus subsequently gradually shuts off genes, entering latency II and eventually latency I. In latency I, only one protein and some non-coding RNAs are expressed. The protein, EBNA-1, binds to a replication origin in the viral genome and is instrumental in securing synthesis of DNA when the host cell divides. Lytic gene products are also produced in three consecutive stages: immediate-early, early, and late The primary role of the immediate-early lytic products is to function as transactivators, enhancing the expression of later lytic genes.
The early lytic products take on more diverse functions, such as replication, metabolism, and blockade of antigen processing. The late lytic products are typically proteins with structural roles, including the units of the capsid and glycoproteins that are incorporated in the viral envelope. The actual changes in both viral and host cell transcription and translation over the various stages of viral latency and reactivation are highly complex, as demonstrated with various functional genomics studies on CMV Herpesviruses, being enveloped, normally bud from the cell membrane, which implies that lysis of the cell is not required.
However, the takeover necessary for running active production of viral particles in epithelial cells or leukocytes typically results in cell death. In the case of HSVs, much of our knowledge of the molecular control of latency comes from studies with virus in cultured neuronal cells Here axonal transport plays an important role.
If the virus first enters at a distant spot on an axon, as compared to closer to the cell body, the situation favors latency. The explanation may be inefficient axonal transport of virion-associated regulatory factors, such as the HSV lytic initiator protein VP16 The protein is released from the viral particle upon entry, and subsequently requires independent transport to the nucleus in order to initiate the replicative program.
Thus, if the distance to the cell body is large, less VP16 will reach the nucleus, and the onset of viral productivity is compromised. Later on, other factors may initiate de novo synthesis of VP16 in the nucleus thus causing reactivation. Herpesviruses are known for their ability to establish lifelong infections. In order to do so they require a strategy for immune evasion, consequently the viruses have evolved a variety of ways to manipulate the immune system of the host.
One typical example is based on molecular mimicry. Most of the viruses encode homologs of cellular interleukins IL , chemokines, or chemokine receptors Another strategy for immune evasion is to reduce the presentation of viral antigens via the major histocompatibility complex MHC of infected cells The manipulation of the immune system offers the reactivated virus at least partial relief from immune surveillance.
It is, however, a feature that increases the risk of the balance tipping toward excessive viral productivity, which is not in the interest of the virus as it can lead to death or serious disability of the host. Evolution apparently has balanced this possibility, leading to a situation where the viral activity in a normal host is limited to a considerable extent by immune surveillance.
The point is substantiated by the observation that compromised immunity, as in the case of patients receiving immune suppressants, often lead to a drastic increase in viral activity Other data suggest that herpesviruses can in fact form a symbiotic relationship with their hosts. In a mouse model, it has been shown that the systemic activation of macrophages and the prolonged production of interferon-gamma initiated by herpesviral infections protect against subsequent disease caused by the highly pathogenic bacteria Listeria monocytogenes and Yersinia pestis The suggestion of symbiosis is plausible as it is obviously not in the interest of the virus to have their host succumb to other infections.
In animal models, and most likely in humans as well, reactivation of various herpesviruses can be induced by local trauma e. An example of the latter is to elevate the body temperature of mice to 43 o C for 10 min The appearance of HSV cold sores correlates with a wide range of stressors, including mental tension, fatigue, and exposure to bright light More than years ago it was shown that applying trauma to a nerve, for example in connection with the treatment of chronic pain, can lead to an outbreak of herpes in the dermatome associated with the nerve Other cell stressors, such as transient interruption of protein synthesis or hypoxia, are sufficient to induce viral activity — an effect that may be mediated by the disruption of mTOR kinase activity This enzyme has a central role in responding to nutritional or to stress-related cellular events by impacting on mRNA translation.
Apparently, in the case of HSV, it is sufficient to inhibit mTOR by chemical means in the distal part of an axon; a signal causing viral reactivation is then sent to the cell body harboring the viral episome. Presumably, a skin trauma affecting the nerve endings of infected neurons may cause a similar reactivation.
In order to maintain latency, the neuron must be functional, active, and healthy. In cell culture systems, it is also possible to induce reactivation by interfering chemically in ways that impact on gene activity, using compounds that for example block histone methylation or appropriately designed interfering RNAs The question is what factors cause a similar impact on gene expression in vivo.
As to HSV, it is known that environmental triggers such as emotional stress, fever, UV exposure, hormonal changes, dental surgery, and cranial trauma can cause activation 30 ; but it is not known whether these stimuli act directly on the infected neuron, or indirectly by means of bodily functions.
These cells are often found in association with infected neurons, sometimes connected to the neuron via immunological synapses. They produce interferons and related factors that presumably contribute to the maintenance of latency and at the same time help the neuron survive In the case of EBV, the latent virus harbored in B-cells can be reactivated in vitro by stimulating B-cell receptors, suggesting that reactivation in vivo may occur when the infected B-cell responds to unrelated infections The point may help explain why reactivation of EBV occasionally appears as a secondary infection.
The aging immune system is no longer able to control the virus efficiently leading to a more chronic, slow-and-low rather than latent type of infection A range of deteriorative immunological changes are expected to correlate with aging, but it is not known exactly what causes the concomitant increase in herpesvirus activity.
In fact, the stress associated with space flight is sufficient to cause reactivation of latent herpesviruses, presumably by downregulating cellular immunity 46 ; which suggests that even a minor decline, or change, in immunological function may be enough.
This point is also reflected in the observation that it makes considerable difference whether the individual is first infected as an infant or in puberty, as exemplified by the case of EBV and mononucleosis. In other words, when CMV and possibly other herpesviruses gradually produces more viral proteins and particles, the concomitant attempt of counteracting the situation by an aging immune system can demote the capacity to fight these viruses.
We have considerable knowledge of the various pathways of molecular signaling that can lead to reactivation, and we have empirical information of environmental triggers doing the same.
What we do not know is which molecular or cellular pathways the environmental factors use. It could be through some of the options outlined by, mostly in vitro , experiments; or it could be novel mechanisms.
Apparently, viral activity depends on a delicate balance of constraining and activating factors. Minor disturbances that upset this balance seem sufficient to lead the virus toward production of progeny, and presumably this disturbance can result from a variety of effectors.
In most cases, reactivation does not lead to serious disease. It is sufficient for the virus to be shed in the oral cavity, and even HSV appears in the saliva in the absence of sores Then again the level of viral activity most likely correlates with clinical symptoms. Innate and acquired host factors will affect the balance between viral activity and immune surveillance, making some people more susceptible to problematic infections than others.
In this context, it should be mentioned that we tend to attribute guilt by association. If symptoms correlate with the detection of virus, we tend to assume that the virus is responsible. This may lead to a faulty diagnosis and suboptimal treatment. The herpesviruses are likely to be reactivated as a consequence of a variety of conditions, but they are not necessarily involved in the underlying etiology. Due to their almost ubiquitous presence and ease of activation, clinical findings and epidemiology may suggest a causative role, even if the viruses are mere opportunists.
The delicate balance between latency and reactivation is designed by evolution. In a normal host, experiencing the normal interaction with the virus, the process is tuned to a long-term relationship that does not cause undue harm. However, if environmental factors upset this balance, or if the host for whatever reason is immunocompromised, the virus may inadvertently cause disease. One might speculate that the optimal strategy for counteracting disease is to encourage early life exposure to herpesviruses.
For the average person, infant inoculation with EBV and CMV may be beneficial, but the strategy does imply a risk for disease in rare individuals. Moreover, we live to an age where it is expected that the immune system has reduced potential, and occasionally we need to subdue the system in connection with various treatments. Thus, harmful consequences of these viruses are likely to occur at some point in life. One alternative is vaccines.
The more commonly used alternative at the present is medication. Fortunately, we have a considerable pharmaceutical arsenal to fight these viruses 9 , unfortunately these medicines are unlikely to rid the body of virus. There is no conflict of interest in the present study for any of the author. National Center for Biotechnology Information , U. Journal List J Oral Microbiol v. J Oral Microbiol. Published online Oct Author information Article notes Copyright and License information Disclaimer.
Email: on. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Keywords: herpes simplex, Epstein—Barr, cytomegalovirus, varicella zoster, reemergence, immune defense, viral pathology, oral cavity.
Herpesviruses — biology and pathology The human herpesviruses are large typically — nm , enveloped i. Open in a separate window. Table 1 Key properties of human herpesviruses. Herpes simplex virus HSV-1 is primarily associated with blisters, referred to as cold sores, or herpes labialis , on the lips. Varicella zoster virus The VZV is related to the HSV both in evolutionary terms and in cell tropism and, as might be expected, the clinical picture has shared characteristics.
Epstein—Barr virus and cytomegalovirus EBV and CMV belong to respectively the gamma and beta subfamily of Herpesviridae , yet the clinical picture is related. Human herpesvirus -6, -7 and -8 Human herpesviruses HHVs -6—8 were discovered relatively late. Viral strategy An act of balance The emerging picture, of the natural biology of herpesviruses, is a primary infection with mild or no symptoms, and a highly successful establishment of a long-term relationship with the host.
The role of the oral cavity The oral cavity plays a vital role in the transmission of a large range of viruses including most human herpesviruses. Latency and reactivation Features associated with latency and reactivation Reactivation is a dangerous option for the virus. Viral impact on immune surveillance Herpesviruses are known for their ability to establish lifelong infections. External factors involved in reactivation In animal models, and most likely in humans as well, reactivation of various herpesviruses can be induced by local trauma e.
Concluding remarks We have considerable knowledge of the various pathways of molecular signaling that can lead to reactivation, and we have empirical information of environmental triggers doing the same. Conflict of interest and funding There is no conflict of interest in the present study for any of the author.
References 1. Longitudinal observation of enterovirus and adenovirus in stool samples from Norwegian infants with the highest genetic risk of type 1 diabetes. J Clin Virol. Longitudinal observation of parechovirus in stool samples from Norwegian infants. J Med Virol. Clearance of influenza virus infections by T cells: risk of collateral damage? Curr Opin Virol. B-virus Cercopithecine herpesvirus 1 infection in humans and macaques: potential for zoonotic disease.
Emerg Infect Dis. Hricova M, Mistrikova J. Murine gammaherpesvirus 68 serum antibodies in general human population. Acta Virol. Lindemann D, Rethwilm A. Foamy virus biology and its application for vector development. Molecular epidemiology of TTV-like mini virus in Norway.
Arch Virol. Decoding human cytomegalovirus. Management of herpesvirus infections. Int J Antimicrob Agents. Beigi RH. Viral meningitis Viral Meningitis Viral meningitis tends to be less severe than acute bacterial meningitis. Findings include headache, fever, and nuchal rigidity.
Diagnosis is by cerebrospinal fluid CSF analysis. It is usually self-limited. Lumbosacral myeloradiculitis, typically caused by HSV-2, can occur during primary infection or reactivation of HSV-2 infection and can result in urinary retention or obstipation.
Laboratory confirmation can be helpful, especially if infection is severe, the patient is immunocompromised or pregnant, or lesions are atypical. A Tzanck test a superficial scraping from the base of a freshly ruptured vesicle stained with Wright-Giemsa stain often reveals multinucleate giant cells in HSV or varicella-zoster virus infection. Definitive diagnosis is with culture, seroconversion involving the appropriate serotype in primary infections , PCR, and antigen detection.
Fluid and material for culture should be obtained from the base of a vesicle or of a freshly ulcerated lesion.
HSV can sometimes be identified using direct immunofluorescence assay of scrapings of lesions. HSV should be distinguished from herpes zoster Herpes Zoster Herpes zoster is infection that results when varicella-zoster virus reactivates from its latent state in a posterior dorsal root ganglion. Symptoms usually begin with pain along the affected Clusters of vesicles or ulcers on an erythematous base are unusual in genital ulcers other than those due to HSV infection.
Usually acyclovir , valacyclovir , or famciclovir. For keratitis, topical trifluridine typically in consultation with an ophthalmologist. Treating primary HSV infection with drugs, even if done early, does not prevent the possibility of recurrence. Acyclovir , valacyclovir , or famciclovir can be used to treat infection, especially when it is primary. Infection with acyclovir -resistant HSV is rare and occurs almost exclusively in immunocompromised patients.
Foscarnet may be effective for acyclovir -resistant infections. Secondary bacterial infections are treated with topical antibiotics eg, mupirocin or neomycin - bacitracin or, if severe, with systemic antibiotics eg, penicillinase-resistant beta-lactams.
Systemic analgesics may help. Gingivostomatitis and pharyngitis may require symptom relief with topical anesthetics eg, dyclonine , benzocaine , viscous lidocaine. NOTE: Lidocaine must not be swallowed because it anesthetizes the oropharynx, the hypopharynx, and possibly the epiglottis. Children must be watched for signs of aspiration.
Severe cases can be treated with acyclovir , valacyclovir , or famciclovir. Herpes labialis responds to oral and topical acyclovir. Toxicity appears to be minimal.
Famciclovir mg as one dose or valacyclovir 2 g orally every 12 hours for 1 day can be used to treat recurrent herpes labialis.
Acyclovir -resistant strains are resistant to penciclovir , famciclovir , and valacyclovir. Herpetic whitlow heals in 2 to 3 weeks without treatment. Topical acyclovir has not been shown to be effective. Oral or IV acyclovir can be used in immunosuppressed patients and those with severe infection.
Treatment of herpes simplex keratitis Treatment Herpes simplex keratitis is corneal infection with herpes simplex virus. Treatment for 14 to 21 days is preferred to prevent potential relapse. Viral meningitis is usually treated with IV acyclovir. Acyclovir is generally very well-tolerated. However, adverse effects can include phlebitis, renal dysfunction, and, rarely, neurotoxicity lethargy, confusion, seizures, coma. HSV usually causes mucocutaneous infection but sometimes causes keratitis, and serious CNS infection can occur in neonates and in adults.
After initial infection, HSV remains dormant in nerve ganglia, from which it can periodically emerge, causing symptoms. Diagnose mucocutaneous infections clinically, but do viral culture, PCR, or antigen detection if patients are neonates, immunocompromised, or pregnant or have a CNS infection or severe disease. For mucocutaneous infections, consider oral acyclovir , valacyclovir , or famciclovir ; for herpes labialis, an alternative is topical penciclovir or docosanol.
From developing new therapies that treat and prevent disease to helping people in need, we are committed to improving health and well-being around the world. Most infected persons may be unaware of their infection; in the United States, an estimated Infections are transmitted through contact with HSV in herpes lesions, mucosal surfaces, genital secretions, or oral secretions.
However, receiving oral sex from a person with an oral HSV-1 infection can result in getting a genital HSV-1 infection. Most individuals infected with HSV are asymptomatic or have very mild symptoms that go unnoticed or are mistaken for another skin condition. The average incubation period for an initial herpes infection is 4 days range, 2 to 12 after exposure. Clinical manifestations of genital herpes differ between the first and recurrent i.
The first outbreak of herpes is often associated with a longer duration of herpetic lesions, increased viral shedding making HSV transmission more likely and systemic symptoms including fever, body aches, swollen lymph nodes, or headache.
Genital herpes may cause painful genital ulcers that can be severe and persistent in persons with suppressed immune systems, such as HIV-infected persons. Some persons who contract genital herpes have concerns about how it will impact their overall health, sex life, and relationships. One resource can be found here: www.
There are also potential complications for a pregnant woman and her newborn child. Genital ulcerative disease caused by herpes makes it easier to transmit and acquire HIV infection sexually. There is an estimated 2- to 4-fold increased risk of acquiring HIV, if individuals with genital herpes infection are genitally exposed to HIV.
In persons with both HIV and genital herpes, local activation of HIV replication at the site of genital herpes infection can increase the risk that HIV will be transmitted during contact with the mouth, vagina, or rectum of an HIV-uninfected sex partner. Neonatal herpes is one of the most serious complications of genital herpes. Women should be counseled to abstain from intercourse during the third trimester with partners known to have or suspected of having genital herpes.
While women with genital herpes may be offered antiviral medication late in pregnancy through delivery to reduce the risk of a recurrent herpes outbreak, third trimester antiviral prophylaxis has not been shown to decrease the risk of herpes transmission to the neonate. HSV nucleic acid amplification tests NAAT are the most sensitive and highly specific tests available for diagnosing herpes.
However, in some settings viral culture is the only test available. The sensitivity of viral culture can be low, especially among people who have recurrent or healing lesions. Because viral shedding is intermittent, it is possible for someone to have a genital herpes infection even though it was not detected by NAAT or culture. Type-specific virologic tests can be used for diagnosing genital herpes when a person has recurrent symptoms or lesion without a confirmatory NAAT, culture result, or has a partner with genital herpes.
Both virologic tests and type-specific serologic tests should be available in clinical settings serving patients with, or at risk for, sexually transmitted infections. If confirmatory tests are unavailable, patients should be counseled about the limitations of available testing before serologic testing.
Healthcare providers should also be aware that false-positive results occur. In instances of suspected recent acquisition, serologic testing within 12 weeks after acquisition may be associated with false negative test results.
HSV-1 serologic testing does not distinguish between oral and genital infection, and typically should not be performed for diagnosing genital HSV-1 infection. Diagnosis of genital HSV-1 infection is confirmed by virologic tests from lesions. Patients who are at higher risk of infection e. There is no cure for herpes. Antiviral medications can, however, prevent or shorten outbreaks during the period of time the person takes the medication.
There is currently no commercially available vaccine that is protective against genital herpes infection. Candidate vaccines are in clinical trials.
Correct and consistent use of latex condoms can reduce, but not eliminate, the risk of transmitting or acquiring genital herpes because herpes virus shedding can occur in areas that are not covered by a condom. The surest way to avoid transmission of STDs, including genital herpes, is to abstain from sexual contact, or to be in a long-term mutually monogamous relationship with a partner who has been tested for STDs and is known to be uninfected. Persons with herpes should abstain from sexual activity with partners when herpes lesions or other symptoms of herpes are present.
It is important to know that even if a person does not have any symptoms, he or she can still infect sex partners.
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