INVITED REVIEW ARTICLE

Herpesviruses: latency and

reactivation
viral strategies
and host response
Bjørn Grinde*
Department of Mental Health, Norwegian Institute of Public Health, Oslo, Norway

Eight members of the Herpesviridae family commonly infect humans, and close to 100% of the adult
population is infected with at least one of these. The five that cause the most health concerns are: herpes
simplex virus (HSV) type 1 and 2, Epstein
Barr virus (EBV), cytomegalovirus (CMV), and varicella zoster
virus (VZV). In addition, there are human herpes virus (HHV) types 6
8. The review starts by introducing
possible viral strategies in general. The particular biology and host relationship of the various human
herpesviruses, including their pathology, are examined subsequently. Factors that contribute to the
maintenance of latency and reactivation of viral replication are discussed. There will be special reference
to how these viruses exploit and contribute to pathology in the oral cavity. Reactivation does not necessarily
imply clinical symptoms, as reflected in the asymptomatic shedding of EBV and CMV from oral mucosa.
The immune response and the level of viral output are both important to the consequences experienced.
Keywords: herpes simplex; Epstein
Barr; cytomegalovirus; varicella zoster; reemergence; immune defense; viral pathology;
oral cavity

Received: 5 September 2013; Revised: 3 October 2013; Accepted: 8 October 2013; Published: 25 October 2013

iral infections are generally recognized only when Viruses that have a long-term evolutionary relationship

V they cause, or are suspected to cause, disease. The

more common scenario is most likely that viral
activity within a host does not result in any clinical
with their host species are normally relatively benign.
These viruses rely on their hosts for replication, thus
evolution has designed the interaction to run smoothly.
symptoms. This point has been demonstrated for a range It is generally not in the evolutionary interest of viruses
of potentially pathogenic viruses by finding a high to kill or seriously maim their residence, as that would
prevalence in healthy individuals (1, 2). It is important impede further progress. Consequently, the more danger-
to keep this in mind when exploring these agents and ous viruses are those with a recent zoonotic history; such
their relationship with the host. as HIV, SARS, Ebola, and avian influenza. The human
When symptoms do occur, they can be classified into herpesviruses most likely have a long evolutionary history
two groups. In the first group, symptoms are induced by of coevolution with our species. Thus, in a normal
the virus for the particular purpose of advancing survival environment, a healthy individual will rarely experience
and propagation. Typical examples are related to the their presence. The main exception being symptoms
transfer of viral particles between individuals, as the related to viral transmission, such as chickenpox blisters
production of viral particles does not necessarily require and herpes cold sores. The point of viral restraint is
any noticeable damage to the host. Coughing, diarrhea, particular relevant for herpesviruses due to their strategy
and cold sore represent viral strategies that presumably of latency. Latent viruses require a host who stays alive
evolved for the purpose of contagion. In the second and is healthy enough to interact with others.
group, symptoms are caused by the host response or There are two known examples of zoonotic herpesvirus
inadvertently by excess viral activity. When the immune infections: the cercopithecine herpesvirus-1 and the
system reacts to foreign antigens, there will be collateral murine gamma herpesvirus. The former has a very high
damage. In some cases, however, the immune system fatality rate due to encephalomyelitis but is fortunately
appears to overreact causing potentially more harm than rare (4); the latter is more common, one study suggests
the virus itself. The response to certain strains of in- a prevalence of 4.5% in a general population, but it is
fluenza virus is a possible example (3). relatively benign (5). This review focuses on the human

Journal of Oral Microbiology 2013. # 2013 Bjørn Grinde. This is an Open Access article distributed under the terms of the Creative Commons Attribution- 1
Noncommercial 3.0 Unported License (http://creativecommons.org/licenses/by-nc/3.0/), permitting all non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited. Citation: Journal of Oral Microbiology 2013, 5: 22766 - http://dx.doi.org/10.3402/jom.v5i0.22766
(page number not for citation purpose)
Bjørn Grinde

herpesviruses. Although all eight subtypes are discussed, If this balance moves too far in the direction of viral
occasionally the focus will be on one or two representa- particles, adverse consequences are likely to occur.
tive examples. This constraint is required for brevity but Torque teno viruses are not known to cause clinical
also reflects limits of the present knowledge. symptoms, yet they are present in the vast majority of
Viruses can be divided into three types relating to their adults (7). The important question is why herpesviruses
replicative strategies. Latency with occasional reemer- occasionally are responsible for considerable pathogeni-
gence is one. Viral latency should not be confused with city. The problem is likely related to the way they are
clinical latency, which is the incubation period in which designed for reactivation from latency; that is, rather than
the virus is active, but symptoms have not yet appeared. a slow-and-low strategy, they have bursts of more
A second option is the ‘hit-and-run’ approach. Influenza vigorous replicative activity. Understanding what regu-
and the diarrhea causing norovirus are typical examples. lates the level of viral productivity, and the immune
They display a rapid burst of replication but are sub- response, may help us find strategies to deal with the
clinical problems.
sequently cleared from the system. They depend on their
hosts to shed large quantities of viral particles in the
hope that some will find the way to novel individuals. The
third option is the ‘slow-and-low’ tactic. These viruses
Herpesviruses
biology and pathology
The human herpesviruses are large (typically 100
200 nm),
enveloped (i.e. membrane-bound) viruses. They contain
replicate continuously, but at a level sufficiently low not
double-stranded DNA genomes packed in an icosahedral
to seriously damage their host or to provoke an immune
protein cage. The various genomes include 70
200 pre-
response of sufficient magnitude to risk expulsion. Hu- dicted open reading frames, thus as to gene diversity they
man spumavirus (6) and torque teno virus (a member of are among the most complex human viruses. Moreover,
Circoviridae that infects humans) (7) appear to follow this the number of open reading frames grossly underestimates
strategy. There is no clear-cut distinction between latency the true genomic output. For example, in the case of
and the slow-and-low approach. Even typically latent cytomegalovirus (CMV), alternative splicing and optional
viruses are not necessarily 100% dormant in-between start codons give rise to more than 700 different viral
outbreaks, and in both cases viral activity will fluctuate. proteins (8). In addition, there are a large number of non-
Whether the virus follows a slow-and-low strategy, or has coding RNAs based on the viral DNA that serve various
cycles of reactivation, the number of viral particles regulatory functions. In Fig. 1 is shown the lifecycle of
present is defined by the balance between viral prolifera- Epstein
Barr virus (EBV) as a typical example of a
tion and the capacity of the immune system for clearance. herpesviral strategy.

Fig. 1. Schematic diagram of EBV replication cycle as an example of a typical herpesviral strategy. Modified from a figure in
Wikimedia Creative Commons, author Graham Colm.

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Citation: Journal of Oral Microbiology 2013, 5: 22766 - http://dx.doi.org/10.3402/jom.v5i0.22766
 Viral strategies and host response of herpesviruses

The large repertoire of herpes genes allows for an Table 1. A review of the management of pathology has
intricate relationship with the host. Not only do these been recently published (9).
viruses manipulate the cells they infect but also the
immune response. Herpes simplex virus
The alpha subfamily (varicella zoster virus [VZV] and HSV-1 is primarily associated with blisters, referred to as
herpes simplex virus [HSV]-1 and -2) primarily target cold sores, or herpes labialis, on the lips. The HSV-2 is
neurons for long-term residency, but they also replicate in associated with related genital sores or blisters; however,
both viruses can cause lesions at either site. In fact, the
epithelia, which is essential for efficient transmission
HSV-1 is today the most common form found in genital
through skin or mucosa. The others (beta and gamma
herpes (10). Sores typically occur a few days after the
subfamilies) prefer various subsets of leukocytes, but
primary infection, and reappear more or less regularly
most of them can also infect epithelial cells. Cell tropism
later in life for a substantial percentage of those infected.
is determined by the presence of cell surface receptors,
The blisters contain abundant viral particles and pre-
as well as by whether the intracellular conditions are sumably represent a main strategy for viral transmission.
supportive for viral activity. In general, the replication Host factors, such as the intensity of the immune res-
takes place within the nucleus. In some host cells, gene ponse, may worsen the symptoms. The viruses take life-
products based on latency-associated transcripts accu- time residency in nerve cells and are transported to the
mulate, which lead to a period of latency. If transcription mucosa along axons. Over time, the episodes tend to
is shifted to lytic products, novel viral particles are diminish in frequency and severity. The genital form is
produced, which typically leads to the death of the cell. less likely to cause recurrent blisters, but the virus may
The reactivation is traditionally associated with malaise still be shed through the mucosa.
but does not necessarily lead to any notable symptoms. The mucosal sores are the common sign of an active
Below are outlined the main clinical outcomes for the infection, but HSV can also produce cutaneous lesions,
various viral types. An overview of the viruses is shown in particularly around the nails of fingers and toes, a

Table 1. Key properties of human herpesviruses

Trivial name Oral Other Primary Main sites

and acronym Formal name Type affection pathology target cells of latency

Herpes simplex Human Alpha Cold sores Genital ulcers, related Mucoepithelia Sensory and
virus-1 (HSV-1) herpesvirus 1 (herpes ulcers) skin lesions, keratitis, cranial nerve
encephalitis, meningitis ganglia
Herpes simplex Human Alpha Cold sores Genital ulcers, as Mucoepithelia Sensory and
virus-2 (HSV-2) herpesvirus 2 (herpes ulcers) HSV-1 but more rare cranial nerve
ganglia
Varicella zoster Human Alpha Possible oral Chicken pox, herpes Mucoepithelia Sensory and
virus (VZV) herpesvirus 3 manifestation of zoster cranial nerve
chicken pox and ganglia
herpes zoster
Epstein
Barr Human Gamma Hairy leukoplakia, Mononucleosis, Epithelial and Memory B-cells
virus (EBV) herpesvirus 4 periodontitis, lymphoma B-cells
nasopharyngeal
carcinoma
Cytomegalovirus Human Beta Periodontitis? Mononucleosis Monocytes, Monocytes,
(CMV) herpesvirus 5 lymphocytes lymphocytes
and epithelia
Roseola virus Human Beta Roseola in infants T-cells Various
(HHV-6) herpesvirus leukocytes
6A and 6B
Roseola virus Human Beta Roseola in infants T-cells T-cells, epithelia
(HHV-7) herpesvirus 7
Kaposi’s sarcoma- Human Gamma Kaposi’s sarcoma Probably B-cells
associated virus herpesvirus 8 lymphocytes
(HHV-8) and epithelia

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Bjørn Grinde

condition referred to as herpetic whitlow (11). In the sociation with AIDS, the virus may cause oral hairy
absence of gloves, it used to be a common problem for leukoplakia, a condition characterized by white patches
dental workers (12). HSV can also reach the eyes causing typically on the lateral surface of the tongue (17).
keratitis, which may lead to blindness (13). Based on their If the host is unable to keep these viruses at bay, they
affinity for neurons and epithelial cells they may attack may also contribute to periodontitis (18, 19). This point
the brain resulting in encephalitis or meningitis (14). has been indicated by the successful treatment of a patient,
Whereas the mucosal and cutaneous symptoms have suffering from severe periodontitis, with valacyclovir (20).
obvious significance for viral transmission, the activity The patient did not respond to traditional treatment, and
in the brain appears to be an incongruity. It may reflect prior to the use of valacyclovir there were exceptionally
stress factors in the host causing demoted immune high levels of EBV in affected periodontal pockets, which
surveillance. disappeared following 10 days of medication.

Varicella zoster virus Human herpesvirus -6, -7 and -8

The VZV is related to the HSV both in evolutionary Human herpesviruses (HHVs)-6
8 were discovered rela-
terms and in cell tropism and, as might be expected, the tively late. As with the other herpesviruses, at least types 6
clinical picture has shared characteristics. The primary and 7, often referred to as roseola viruses, can form skin
infection with VZV normally results in chickenpox. The lesions; in this case referred to as exanthema subitum or
disease is typically accompanied by malaise, such as low- roseola infantum (21). The condition is usually seen only in
grade fever, nausea, aching muscles, and headache. It infants less than 2 years of age. The onset is characterized
starts with a vesicular, itchy rash that primarily affects the by sudden high fever. As the fever subsides, a red rash
trunk and the head. VZV may also form ulcers in the oral appears. It usually begins on the trunk, but spreads to the
cavity. legs and neck. Although only some 30% develop symp-
The clinical picture is somewhat different if the virus is toms, the vast majority of infants 2 to 4 years old harbor
reactivated later in life. The disease is then referred to as the virus (21).
herpes zoster or shingles. In both cases, the virus causes HHV-8 is associated with Kaposi’s sarcoma, a form of
skin rash with blistering, but in the recurrent form cancer that became known through its diagnosis in
typically on a more limited area of the body. Apparently, patients with AIDS (22). The virus is common in sub-
the immune system prevents a more global viral activity Saharan Africa but rarer in other parts of the world.
but is unable to avert a limited number of nerve cells from Presumably, the majority of those infected show no
producing virus that are brought to the terminating area symptoms.
of their axons; that is, to a particular dermatome (15).
As in the case with HSV, VZV is also known to cause Viral strategy
encephalitis.
An act of balance


Epstein Barr virus and cytomegalovirus
EBV and CMV belong to respectively the gamma and
The emerging picture, of the natural biology of herpes-
viruses, is a primary infection with mild or no symptoms,
beta subfamily of Herpesviridae, yet the clinical picture is and a highly successful establishment of a long-term
related. EBV primarily infects B-cells, whereas CMV is relationship with the host. Viral activity may be asso-
designed to enter monocytes besides lymphocytes. Both ciated with lesions either in the skin, the oral cavity, or
of them also infect epithelial cells. They cause mono- genital region as a means of transmitting viral particles to
nucleosis, or mononucleosis-like symptoms, although the novel hosts. The normal course of host
viral relation-
condition is more commonly associated with EBV. The ship implies a well-regulated viremia and thus limited
illness is most prevalent in adolescents, where it is malaise. However, certain factors cause this evolutionary-
referred to as kissing disease based on a typical route of designed, benign relationship to fault.
transmission. The condition manifests itself with fever, For one, the design is tuned to a ubiquitous presence of
sore throat, fatigue, and swollen lymph nodes. Presum- viruses in the population, and the acquisition of virus at
ably, it is a consequence of the inability of the immune an early age. As such, they may be referred to as part of
system to handle the virus in an appropriate fashion at a normal, microbiotic flora; although in ancient times
this stage of life. Those who first encounter these viruses all subtypes were probably not present in all human
as infants rarely develop symptoms. subpopulations. An elevated level of hygiene in indus-
Congenital infection with CMV is one of the leading trialized societies restricts this early transmission. When
viral causes of birth defects (16). EBV, however, is known people are affected at a later stage in life, the immune
to be tumorigenic. It is associated with various forms of system has taken on a somewhat different quality. The
lymphomas as well as with nasopharyngeal carcinomas. resulting misbalance of viral activity may cause diseases,
In immunocompromised individuals, particularly in as- of which mononucleosis presumably is a typical example.

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 Viral strategies and host response of herpesviruses

Not only do these patients experience more malaise than mouth contribute further to the role of the human mouth
infected infants but they are also at higher risk for in the transmission of pathogens. Biting is still considered
recurrent problems later in life (23). to be a relevant risk factor in the transfer of viruses from
The balance between viral activity and immune sup- other primates (28).
pression may also be compromised if the quality of Viruses such as EBV and CMV are common in the oral
immune surveillance is reduced, particularly in cases of a mucosa (18, 19), but also HSV, HHV-6 and HHV-7 can be
depressed T-cell immune function. This is a problem for shed from a healthy oral mucosa (24). Apparently, all
people who suffer from innate or acquired immune herpesviruses have evolved the capacity to access the oral
deficiency, the latter exemplified by AIDS. Patients who cavity. EBV, CMV, and HHV-6
8 replicate in epithelium
receive organ transplants are generally given immuno- cells or various leukocytes where the latter can infiltrate
suppressant medicines that produce a related effect (24). the mucosa. VZV, and HSV-1 and -2 are latent in neurons,
Physical or psychological stress (25), and the reduction but the viral particles are transported via axons to mucosa
in bodily functions associated with aging (26), may be where the virus may continue replicating in epithelial cells.
sufficient to disturb the delicate balance between viral It should be noted that using the mouth as part of the
activity and immune response. strategy for viral contagion does not require the forma-
In addition to the problems related to increased viral tion of sores, blisters, or other visible changes in the
load, some herpesvirus, notably EBV and HHV-8, are mucosa. However, clinical symptoms associated with the
associated with cancer. Most viruses that reproduce in the mucosa generally imply a higher abundance of viral
nucleus require the presence of host factors associated particles, and thus a boosted chance of transmission.
with replication and transcription; thus viral replication
is, to a lesser or greater extent, dependent on mitotic Latency and reactivation
activation of the cell they inhabit. Moreover, the herpes-
viruses manufacture gene products aimed at helping Features associated with latency and reactivation
the cell survive; an effect that is at least partly due to Reactivation is a dangerous option for the virus. An active
microRNAs produced from the viral genome and acting replication will tend to induce various host mechanisms,
as regulators of cellular genes (27). EBV in particular involving either the immune system or internal signaling
produces factors in the early phase of infection that lead in the cell, leading to the death of the infected cell. For
to the immortalization of B-lymphocytes (24). This every viral genome that successfully produces infective
strategy of stimulating the cell requires a fine balance. progeny, several viruses probably initiate this process, but
If the physiology of the cell tips too far in the direction of fail at some point along the way.
growth, the result may be uncontrolled cell division, that In order to establish latency, the viral genome is
is, cancer. The problem is rarely an issue for viruses that circularized to form an episomal DNA element packed
target neurons, as these cells are more permanently left in in histones (29). For lytic activation to occur, the genome
a non-replicative state. However, the lymphocytes and must be linearized (30). During latency, the viral DNA is
epithelial cells are more tuned toward replication; and copied by cellular DNA polymerases, along with the
consequently more in danger of having the balance meant chromosomes, preferably when the cell engages in mitosis.
to control cell growth overthrown. It should be noted that This contrasts with lytic replication in which the viral
compared to the prevalence of the herpesviruses, this DNA polymerase is engaged, reflecting a viral takeover
unfortunate event (for both host and virus) is rare. of the cell. For latency, the virus relies on the host’s epi-
genetic mechanisms for the silencing of viral genes, such
The role of the oral cavity as packaging of the DNA in particular types of histones
The oral cavity plays a vital role in the transmission of a and specific methylation programs (30). Presumably it is
large range of viruses including most human herpes- safer to keep the production of viral proteins to a mini-
viruses. The crucial issue seems to be that the oral mucosa mum during latency in order to avoid immune surveil-
has certain preferred features compared to skin or genital lance; but at the same time it is important for the virus to
mucosa: The mouth offers more efficient transmission be copied in order to maintain long-term presence, as
because the virus can be dispersed in aerosols, either some of the daughter cells will eventually die.
released by normal breathing, but more efficiently pro- The viral genome is not completely silenced. Latent
duced upon coughing or spitting. Moreover, as enveloped EBV, for example, expresses a small portion of its genes
viruses, the herpes family requires moisture for survival. (31). The virus exhibits three different latency programs,
The blisters on the skin serve the purpose as long as each comprising a limited and distinct set of viral
they are watery, but the virus relies on skin-to-skin contact proteins and RNAs (32, 33). Upon infecting a resting
with another person, or immediate contact between B-cell, the virus starts with the more comprehensive
objects touched by the infected person and the next latency III program. The resulting proteins induce the
host. The occurrence of kissing and food sharing by B-cell to proliferate. The virus subsequently gradually

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shuts off genes, entering latency II and eventually latency for immune evasion is to reduce the presentation of
I. In latency I, only one protein and some non-coding viral antigens via the major histocompatibility complex
RNAs are expressed. The protein, EBNA-1, binds to a (MHC) of infected cells (38). Some viruses simply
replication origin in the viral genome and is instrumental downregulate or inhibit the display of both MHC class
in securing synthesis of DNA when the host cell divides. I and II molecules. The EBV-encoded BNLF2a gene
Lytic gene products are also produced in three con- reduces antigen presentation, and consequently recogni-
secutive stages: immediate-early, early, and late (23). The tion by CD8 T-cells, in newly infected cells (37).
primary role of the immediate-early lytic products is to The manipulation of the immune system offers the
function as transactivators, enhancing the expression of reactivated virus at least partial relief from immune
later lytic genes. The early lytic products take on more surveillance. It is, however, a feature that increases the
diverse functions, such as replication, metabolism, and risk of the balance tipping toward excessive viral produc-
blockade of antigen processing. The late lytic products tivity, which is not in the interest of the virus as it can
are typically proteins with structural roles, including the lead to death or serious disability of the host. Evolution
units of the capsid and glycoproteins that are incorpo- apparently has balanced this possibility, leading to a
rated in the viral envelope. Other late gene products, such situation where the viral activity in a normal host is
as BCRF1, help EBV evade the immune system. The limited to a considerable extent by immune surveillance.
actual changes in both viral and host cell transcription The point is substantiated by the observation that
and translation over the various stages of viral latency compromised immunity, as in the case of patients receiv-
and reactivation are highly complex, as demonstrated ing immune suppressants, often lead to a drastic increase
with various functional genomics studies on CMV (34). in viral activity (24).
Herpesviruses, being enveloped, normally bud from the Other data suggest that herpesviruses can in fact form
cell membrane, which implies that lysis of the cell is not a symbiotic relationship with their hosts. In a mouse
required. However, the takeover necessary for running model, it has been shown that the systemic activation of
active production of viral particles in epithelial cells or macrophages and the prolonged production of inter-
leukocytes typically results in cell death. feron-gamma initiated by herpesviral infections protect
In the case of HSVs, much of our knowledge of the against subsequent disease caused by the highly patho-
molecular control of latency comes from studies with genic bacteria Listeria monocytogenes and Yersinia pestis
virus in cultured neuronal cells (30). Here axonal trans- (39). The suggestion of symbiosis is plausible as it is
port plays an important role. If the virus first enters at a obviously not in the interest of the virus to have their host
distant spot on an axon, as compared to closer to the cell succumb to other infections.
body, the situation favors latency. The explanation may
be inefficient axonal transport of virion-associated reg- External factors involved in reactivation
ulatory factors, such as the HSV lytic initiator protein In animal models, and most likely in humans as well,
VP16 (35). The protein is released from the viral particle reactivation of various herpesviruses can be induced by
upon entry, and subsequently requires independent trans- local trauma (e.g. in the form of surgery) or systemic
port to the nucleus in order to initiate the replicative stress. An example of the latter is to elevate the body
program. Thus, if the distance to the cell body is large, temperature of mice to 438C for 10 min (40). The
less VP16 will reach the nucleus, and the onset of viral appearance of HSV cold sores correlates with a wide
productivity is compromised. Later on, other factors may range of stressors, including mental tension, fatigue, and
initiate de novo synthesis of VP16 in the nucleus thus exposure to bright light (41). More than 100 years ago it
causing reactivation. was shown that applying trauma to a nerve, for example in
connection with the treatment of chronic pain, can lead to
Viral impact on immune surveillance an outbreak of herpes in the dermatome associated with
Herpesviruses are known for their ability to establish the nerve (30).
lifelong infections. In order to do so they require a Other cell stressors, such as transient interruption
strategy for immune evasion, consequently the viruses of protein synthesis or hypoxia, are sufficient to induce
have evolved a variety of ways to manipulate the immune viral activity
an effect that may be mediated by the
system of the host. One typical example is based on disruption of mTOR kinase activity (42). This enzyme
molecular mimicry. Most of the viruses encode homologs has a central role in responding to nutritional or to stress-
of cellular interleukins (IL), chemokines, or chemokine related cellular events by impacting on mRNA transla-
receptors (36). The EBV gene BCRF1, for example, tion. Apparently, in the case of HSV, it is sufficient to
encodes a viral homolog of human IL-10 (37). The viral inhibit mTOR (by chemical means) in the distal part of
version of IL-10 impairs NK cell mediated killing of an axon; a signal causing viral reactivation is then sent to
infected B-cells, interferes with CD4 T-cell activity, and the cell body harboring the viral episome. Presumably,
modulates cellular cytokine response. Another strategy a skin trauma affecting the nerve endings of infected

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 Viral strategies and host response of herpesviruses

neurons may cause a similar reactivation. In order to counteracting the situation by an aging immune system
maintain latency, the neuron must be functional, active, can demote the capacity to fight these viruses.
and healthy. Similar to rats, the virus prepares to ‘leave
the ship’ if it is likely to ‘sink’. Concluding remarks
In cell culture systems, it is also possible to induce We have considerable knowledge of the various pathways
reactivation by interfering chemically in ways that impact of molecular signaling that can lead to reactivation, and
on gene activity, using compounds that for example block we have empirical information of environmental triggers
histone methylation or appropriately designed interfering doing the same. What we do not know is which molecular
RNAs (30). The question is what factors cause a similar or cellular pathways the environmental factors use. It
impact on gene expression in vivo. As to HSV, it is known could be through some of the options outlined by, mostly
that environmental triggers such as emotional stress, in vitro, experiments; or it could be novel mechanisms.
fever, UV exposure, hormonal changes, dental surgery, Apparently, viral activity depends on a delicate balance of
and cranial trauma can cause activation (30); but it is not constraining and activating factors. Minor disturbances
known whether these stimuli act directly on the infected that upset this balance seem sufficient to lead the virus
neuron, or indirectly by means of bodily functions. toward production of progeny, and presumably this dis-
One possible mechanism for the effect of mental turbance can result from a variety of effectors.
stressors is via virus-specific CD8 T-cells. These cells In most cases, reactivation does not lead to serious
are often found in association with infected neurons, disease. It is sufficient for the virus to be shed in the oral
sometimes connected to the neuron via immunological cavity, and even HSV appears in the saliva in the absence
synapses. They produce interferons and related factors of sores (48). Then again the level of viral activity most
that presumably contribute to the maintenance of latency likely correlates with clinical symptoms. Innate and
and at the same time help the neuron survive (43). Both acquired host factors will affect the balance between viral
mental and physical stressors are known to influence the activity and immune surveillance, making some people
activity of CD8 T-cells through the release of neuroen- more susceptible to problematic infections than others.
docrine factors, a mechanism that may link the control In this context, it should be mentioned that we tend to
of HSV latency to activity in the sympathetic nervous attribute guilt by association. If symptoms correlate with
system (44). In the case of EBV, the latent virus harbored the detection of virus, we tend to assume that the virus
in B-cells can be reactivated in vitro by stimulating B-cell is responsible. This may lead to a faulty diagnosis and
receptors, suggesting that reactivation in vivo may occur suboptimal treatment. The herpesviruses are likely to be
when the infected B-cell responds to unrelated infections reactivated as a consequence of a variety of conditions,
(23). The point may help explain why reactivation of EBV but they are not necessarily involved in the underlying
occasionally appears as a secondary infection. etiology. Due to their almost ubiquitous presence and
The aging immune system is no longer able to control ease of activation, clinical findings and epidemiology may
the virus efficiently leading to a more chronic, slow-and- suggest a causative role, even if the viruses are mere
low rather than latent type of infection (45). A range of opportunists.
deteriorative immunological changes are expected to The delicate balance between latency and reactivation
correlate with aging, but it is not known exactly what is designed by evolution. In a normal host, experiencing
causes the concomitant increase in herpesvirus activity. In the normal interaction with the virus, the process is tuned
fact, the stress associated with space flight is sufficient to to a long-term relationship that does not cause undue
cause reactivation of latent herpesviruses, presumably by harm. However, if environmental factors upset this
downregulating cellular immunity (46); which suggests balance, or if the host for whatever reason is immuno-
that even a minor decline, or change, in immunological compromised, the virus may inadvertently cause disease.
function may be enough. This point is also reflected in One might speculate that the optimal strategy for
the observation that it makes considerable difference counteracting disease is to encourage early life exposure
whether the individual is first infected as an infant or in to herpesviruses. For the average person, infant inocula-
puberty, as exemplified by the case of EBV and mono- tion with EBV and CMV may be beneficial, but the
nucleosis. One probable cause of an increase in EBV strategy does imply a risk for disease in rare individuals.
activity late in life is actually a prior increase in CMV Moreover, we live to an age where it is expected that the
activity. The latter event results in an expansion of immune system has reduced potential, and occasionally
senescent CD8 T-cells which lack CD28, but are we need to subdue the system in connection with various
directed at CMV epitopes; an expansion that has been treatments. Thus, harmful consequences of these viruses
suggested to restrict immune response to other pathogens are likely to occur at some point in life. One alternative is
including EBV (47). In other words, when CMV (and vaccines. We do have a vaccine for VZV, and vaccines are
possibly other herpesviruses) gradually produces more currently under development for HSV (49), EBV (50),
viral proteins and particles, the concomitant attempt of and CMV (51). The more commonly used alternative at

Citation: Journal of Oral Microbiology 2013, 5: 22766 - http://dx.doi.org/10.3402/jom.v5i0.22766 7

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Bjørn Grinde

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Conflict of interest and funding
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Citation: Journal of Oral Microbiology 2013, 5: 22766 - http://dx.doi.org/10.3402/jom.v5i0.22766 9

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