Latent infection virus

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HSV-1 is primarily associated with blisters, referred to as cold sores, or herpes labialis , on the lips. The HSV-2 is associated with related genital sores or blisters; however, both viruses can cause lesions at either site. In fact, the HSV-1 is today the most common form found in genital herpes Sores typically occur a few days after the primary infection, and reappear more or less regularly later in life for a substantial percentage of those infected.

The blisters contain abundant viral particles and presumably represent a main strategy for viral transmission. Host factors, such as the intensity of the immune response, may worsen the symptoms. The viruses take life-time residency in nerve cells and are transported to the mucosa along axons. Over time, the episodes tend to diminish in frequency and severity. The genital form is less likely to cause recurrent blisters, but the virus may still be shed through the mucosa.

The mucosal sores are the common sign of an active infection, but HSV can also produce cutaneous lesions, particularly around the nails of fingers and toes, a condition referred to as herpetic whitlow In the absence of gloves, it used to be a common problem for dental workers HSV can also reach the eyes causing keratitis, which may lead to blindness Based on their affinity for neurons and epithelial cells they may attack the brain resulting in encephalitis or meningitis Whereas the mucosal and cutaneous symptoms have obvious significance for viral transmission, the activity in the brain appears to be an incongruity.

It may reflect stress factors in the host causing demoted immune surveillance. 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.

The primary infection with VZV normally results in chickenpox. The disease is typically accompanied by malaise, such as low-grade fever, nausea, aching muscles, and headache.

It starts with a vesicular, itchy rash that primarily affects the trunk and the head. VZV may also form ulcers in the oral cavity. The clinical picture is somewhat different if the virus is reactivated later in life. The disease is then referred to as herpes zoster or shingles. In both cases, the virus causes skin rash with blistering, but in the recurrent form typically on a more limited area of the body.

Apparently, the immune system prevents a more global viral activity but is unable to avert a limited number of nerve cells from producing virus that are brought to the terminating area of their axons; that is, to a particular dermatome EBV and CMV belong to respectively the gamma and beta subfamily of Herpesviridae , yet the clinical picture is related. Both of them also infect epithelial cells.

They cause mononucleosis, or mononucleosis-like symptoms, although the condition is more commonly associated with EBV. The illness is most prevalent in adolescents, where it is referred to as kissing disease based on a typical route of transmission. The condition manifests itself with fever, sore throat, fatigue, and swollen lymph nodes. Presumably, it is a consequence of the inability of the immune system to handle the virus in an appropriate fashion at this stage of life.

Those who first encounter these viruses as infants rarely develop symptoms. Congenital infection with CMV is one of the leading viral causes of birth defects EBV, however, is known to be tumorigenic. It is associated with various forms of lymphomas as well as with nasopharyngeal carcinomas.

In immunocompromised individuals, particularly in association with AIDS, the virus may cause oral hairy leukoplakia, a condition characterized by white patches typically on the lateral surface of the tongue If the host is unable to keep these viruses at bay, they may also contribute to periodontitis 18 , This point has been indicated by the successful treatment of a patient, suffering from severe periodontitis, with valacyclovir The patient did not respond to traditional treatment, and prior to the use of valacyclovir there were exceptionally high levels of EBV in affected periodontal pockets, which disappeared following 10 days of medication.

Human herpesviruses HHVs -6—8 were discovered relatively late. As with the other herpesviruses, at least types 6 and 7, often referred to as roseola viruses, can form skin lesions; in this case referred to as exanthema subitum or roseola infantum The condition is usually seen only in infants less than 2 years of age.

The onset is characterized by sudden high fever. As the fever subsides, a red rash appears. It usually begins on the trunk, but spreads to the legs and neck. The virus is common in sub-Saharan Africa but rarer in other parts of the world. Presumably, the majority of those infected show no symptoms. 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.

Viral activity may be associated with lesions either in the skin, the oral cavity, or genital region as a means of transmitting viral particles to novel hosts. The normal course of host—viral relationship implies a well-regulated viremia and thus limited malaise.

However, certain factors cause this evolutionary-designed, benign relationship to fault. For one, the design is tuned to a ubiquitous presence of viruses in the population, and the acquisition of virus at an early age. As such, they may be referred to as part of a normal, microbiotic flora; although in ancient times all subtypes were probably not present in all human subpopulations.

An elevated level of hygiene in industrialized societies restricts this early transmission. When people are affected at a later stage in life, the immune system has taken on a somewhat different quality. The resulting misbalance of viral activity may cause diseases, of which mononucleosis presumably is a typical example.

Not only do these patients experience more malaise than infected infants but they are also at higher risk for recurrent problems later in life The balance between viral activity and immune suppression may also be compromised if the quality of immune surveillance is reduced, particularly in cases of a depressed T-cell immune function. This is a problem for people who suffer from innate or acquired immune deficiency, the latter exemplified by AIDS.

Patients who receive organ transplants are generally given immunosuppressant medicines that produce a related effect Physical or psychological stress 25 , and the reduction in bodily functions associated with aging 26 , may be sufficient to disturb the delicate balance between viral activity and immune response.

In addition to the problems related to increased viral load, some herpesvirus, notably EBV and HHV-8, are associated with cancer. Most viruses that reproduce in the nucleus require the presence of host factors associated with replication and transcription; thus viral replication is, to a lesser or greater extent, dependent on mitotic activation of the cell they inhabit.

Moreover, the herpesviruses manufacture gene products aimed at helping the cell survive; an effect that is at least partly due to microRNAs produced from the viral genome and acting as regulators of cellular genes EBV in particular produces factors in the early phase of infection that lead to the immortalization of B-lymphocytes This strategy of stimulating the cell requires a fine balance. If the physiology of the cell tips too far in the direction of growth, the result may be uncontrolled cell division, that is, cancer.

The problem is rarely an issue for viruses that target neurons, as these cells are more permanently left in a non-replicative state. However, the lymphocytes and epithelial cells are more tuned toward replication; and consequently more in danger of having the balance meant to control cell growth overthrown. It should be noted that compared to the prevalence of the herpesviruses, this unfortunate event for both host and virus is rare.

The oral cavity plays a vital role in the transmission of a large range of viruses including most human herpesviruses. The crucial issue seems to be that the oral mucosa has certain preferred features compared to skin or genital mucosa: The mouth offers more efficient transmission because the virus can be dispersed in aerosols, either released by normal breathing, but more efficiently produced upon coughing or spitting.

Moreover, as enveloped viruses, the herpes family requires moisture for survival. The blisters on the skin serve the purpose as long as they are watery, but the virus relies on skin-to-skin contact with another person, or immediate contact between objects touched by the infected person and the next host. The occurrence of kissing and food sharing by mouth contribute further to the role of the human mouth in the transmission of pathogens. Biting is still considered to be a relevant risk factor in the transfer of viruses from other primates Apparently, all herpesviruses have evolved the capacity to access the oral cavity.

VZV, and HSV-1 and -2 are latent in neurons, but the viral particles are transported via axons to mucosa where the virus may continue replicating in epithelial cells. It should be noted that using the mouth as part of the strategy for viral contagion does not require the formation of sores, blisters, or other visible changes in the mucosa.

However, clinical symptoms associated with the mucosa generally imply a higher abundance of viral particles, and thus a boosted chance of transmission.

Reactivation is a dangerous option for the virus. An active replication will tend to induce various host mechanisms, involving either the immune system or internal signaling in the cell, leading to the death of the infected cell. For every viral genome that successfully produces infective progeny, several viruses probably initiate this process, but fail at some point along the way.

In order to establish latency, the viral genome is circularized to form an episomal DNA element packed in histones For lytic activation to occur, the genome must be linearized During latency, the viral DNA is copied by cellular DNA polymerases, along with the chromosomes, preferably when the cell engages in mitosis.

This contrasts with lytic replication in which the viral DNA polymerase is engaged, reflecting a viral takeover of the cell. For latency, the virus relies on the host's epigenetic mechanisms for the silencing of viral genes, such as packaging of the DNA in particular types of histones and specific methylation programs Presumably it is safer to keep the production of viral proteins to a minimum during latency in order to avoid immune surveillance; but at the same time it is important for the virus to be copied in order to maintain long-term presence, as some of the daughter cells will eventually die.

The viral genome is not completely silenced. Latent EBV, for example, expresses a small portion of its genes 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 Mapping genetic elements of Epstein—Barr virus that facilitate extrachromosomal persistence of Epstein—Barr virus-derived plasmids in human cells.

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Epstein—Barr nuclear antigen leader protein coactivates transcription through interaction with histone deacetylase 4. The Epstein—Barr virus transforming protein LMP1 engages signaling proteins for the tumor necrosis factor receptor family. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. The truncated form of the Epstein—Barr virus latent-infection membrane protein expressed in virus replication does not transform rodent fibroblasts.

All three domains of the Epstein—Barr virus-encoded latent membrane protein LMP-1 are required for transformation of rat-1 fibroblasts. Epstein—Barr virus latent membrane protein 1 induces the matrix metalloproteinase-1 promoter via an Ets binding site formed by a single nucleotide polymorphism: enhanced susceptibility to nasopharyngeal carcinoma. Epstein—Barr virus induces invasion and metastasis factors. Anticancer Res. Alterations of biologic properties and gene expression in nasopharyngeal epithelial cells by the Epstein—Barr virus-encoded latent membrane protein 1.

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Epstein—Barr virus latent-infection membrane proteins are palmitoylated and raft-associated: protein 1 binds to the cytoskeleton through TNF receptor cytoplasmic factors.

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Epstein—Barr virus protein LMP2A regulates reactivation from latency by negatively regulating tyrosine kinases involved in sIg-mediated signal transduction. Infect Agents Dis. Epstein—Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Cholesterol is critical for Epstein—Barr virus latent membrane protein 2A trafficking and protein stability.

LMP2A does not require palmitoylation to localize to buoyant complexes or for function. An integral membrane protein LMP2 blocks reactivation of Epstein—Barr virus from latency following surface immunoglobulin crosslinking. Epstein—Barr virus lacking latent membrane protein 2 immortalizes B cells with efficiency indistinguishable from that of wild-type virus.

Epstein—Barr virus latent membrane protein 2A enhances MYC-driven cell cycle progression in a mouse model of B lymphoma. Epstein—Barr virus latent membrane protein 2A exploits Notch1 to alter B-cell identity in vivo. Epstein—Barr virus latent membrane protein 2A and autoimmunity. Trends Immunol. Epstein—Barr virus LMP2A alters in vivo and in vitro models of B-cell anergy, but not deletion, in response to autoantigen. Epstein—Barr virus latent membrane protein 2A contributes to anoikis resistance through ERK activation.

Enrichment of stem-like cell population comprises transformation ability of Epstein—Barr virus latent membrane protein 2A for non-transformed cells. Virus Res. Epstein—Barr virus latent membrane protein-2A-induced DeltaNp63alpha expression is associated with impaired epithelial-cell differentiation.

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Latent membrane protein 2B regulates susceptibility to induction of lytic Epstein—Barr virus infection. Epstein—Barr virus with the latent infection nuclear antigen 3B completely deleted is still competent for B-cell growth transformation in vitro.

Epstein—Barr virus nuclear protein EBNA3C is required for cell cycle progression and growth maintenance of lymphoblastoid cells. A conserved domain of the Epstein—Barr virus nuclear antigens 3A and 3C binds to a discrete domain of Jkappa. The EBV latent antigen 3C inhibits apoptosis through targeted regulation of interferon regulatory factors 4 and 8. Epstein—Barr virus latency in B cells leads to epigenetic repression and CpG methylation of the tumour suppressor gene Bim.

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FEBS Lett. Epstein—Barr virus nuclear antigen 3C recruits histone deacetylase activity and associates with the corepressors mSin3A and NCoR in human B-cell lines.