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JOMSMP-478; No. of Pages 4 ARTICLE IN PRESS

Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

Journal of Oral and Maxillofacial Surgery,

Medicine, and Pathology
journal homepage: www.elsevier.com/locate/jomsmp

Review article

Pathogenesis and life cycle of herpes simplex virus infection-stages of

primary, latency and recurrence
Sreeja P. Kumar a,∗ , Marina Lazar Chandy a , Muhammad Shanavas b , Saba Khan c ,
K.V. Suresh d
a
Department of Oral Medicine & Radiology, Amrita School of Dentistry, Cochin, India
b
Department of Oral Medicine & Radiology, Mahe Institute of Dental Sciences & Hospital, Puducherry, India
c
Department of Oral Medicine & Radiology, Darshan Dental College, Udaipur, India
d
Department of Oral Medicine & Radiology, Segi University, Kuala Lumpur, Malaysia

a r t i c l e i n f o a b s t r a c t

Article history: Aims and objectives: (1) To understand the molecular level mechanism involved in immune evasion lead-
Received 24 September 2015 ing to primary HSV infection. (2) To explain the neuronal latency of herpes simplex virus. (3) To explain
Received in revised form the reason for the specificity in the sites of primary and recurrent HSV lesions.
29 November 2015
Methods: A systematic review was done to understand the molecular level mechanism involved in pri-
Accepted 28 January 2016
mary, latency and recurrent herpes simplex infections. We prepared this article by compiling the data
Available online xxx
from various textbooks, literatures and PubMed, Embase, and EBSCOhost databases.
Results and conclusion: Herpes simplex virus is a highly contagious human pathogen that has widespread
Keywords:
Herpes simplex virus
infections in the oro-facial region which is associated with HSV-1. This single review article can provide
Herpes labialis the entire knowledge about the pathogenesis, its interesting property of latency and clinical features
Virion host shutoff protein of HSV infection under one tree. Thus, this article enlightens the dental professionals with an adequate
knowledge about the pathogenesis, clinical manifestations and specific sites of primary and recurrent
lesions which will highly help them in timely diagnosis, management and also for controlling the spread
of infection.
© 2016 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Pathogenesis of herpes simplex virus infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. Establishment of primary infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.1. Role of virion host shutoff protein (vhs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1.2. Mechanism of immune evasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.2. State of latency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.3. Reactivation of virus and recurrent lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.4. Site specificity for primary and recurrent lesions – role of keratin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Competing interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

夽 Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology;
JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants.
∗ Corresponding author. Tel.: +34 09947320443; fax: +34 976 761767.
E-mail addresses: sreejapk@gmail.com (S.P. Kumar), marinalazarchandy@gmail.com (M.L. Chandy), dr.shanavas.kp@gmail.com (M. Shanavas), dr.sabakhan23@gmail.com
(S. Khan), dr suri88@yahoo.co.in (K.V. Suresh).

http://dx.doi.org/10.1016/j.ajoms.2016.01.006
2212-5558/© 2016 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽

Please cite this article in press as: Kumar SP, et al. Pathogenesis and life cycle of herpes simplex virus infection-stages of primary, latency
and recurrence. J Oral Maxillofac Surg Med Pathol (2016), http://dx.doi.org/10.1016/j.ajoms.2016.01.006
G Model
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Fig. 1. Lifecycle of herpes simplex virus infection.
1. Introduction
Herpes simplex virus (HSV) is a double-stranded DNA virus
which is a member of the Alphaherpesvirinae, a subfamily of the
Herpesviridae family [1]. The name “herpes” is derived from a
Greek word meaning “to creep”. HSV has the subtypes herpes sim-
plex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2)
which causes lesions in the oral cavity and genitalia respectively
[1]. The worldwide prevalence rate of HSV infection is estimated
to be about 65–90% [2]. Herpes simplex virus type 1 is considered
to be a ubiquitous and highly contagious human pathogen which
has high capacity in subverting host cell functions for its own ben-
efit [3]. Blockage of the expression of cellular proteins and efficient
synthesis of viral proteins are effectively done by HSV-1 [4].
2. Pathogenesis of herpes simplex virus infections
There are widespread infections in the oro-facial region caused
by the herpes simplex virus [5]. The infectious cycle of HSV-1 is
highly interesting which includes a primary orolabial infection
mainly occurring on non-keratinized mucosa such as the labial
mucosa and buccal mucosa, less likely developing on keratinized
surfaces like gingiva, hard palate, dorsum of tongue [6]. Follow-
ing the primary infection, the virus ascends the sensory nerve
axons and establishes chronic, latent infection in trigeminal gan-
glia. The dormant virus will be reactivated by various triggering
factors which will then establish the recurrent lesions at the site of
primary infection [7,8] (Fig. 1). HSV is more exposed to sensory neu-
rons innervating the outer layers of skin and mucosa [9]. This is the
reason why recurrent infections are exclusively seen on keratinized
surfaces of skin and mucous membrane [6].
2.1. Establishment of primary infection
There is a spectrum of clinical manifestations caused by HSV-1
infection which can even lead to considerable morbidity and mor-
tality in humans [10]. Primary infection mostly occurs in children
Please cite this article in press as: Kumar SP, et al. Pathogenesis and life cycle of herpes simplex virus infection-stages of primary, latency
and recurrence. J Oral Maxillofac Surg Med Pathol (2016), http://dx.doi.org/10.1016/j.ajoms.2016.01.006
and teenagers. Oral lesions develop following a prodrome of fever,
loss of appetite, malaise and myalgia. The clinical presentation of
oral lesions will be in the form of clusters of vesicles and ulcers
which appear on both keratinized and non-keratinized mucosa.
Vesicles formed will rupture to form ulcers having a scalloped bor-
der and marked surrounding erythema. The disease is self-limiting
and resolves within 10–14 days [11]. The susceptibility to clinical
HSV-1 infection is modulated by polymorphism in genes encoding
HLA class I with combinations of KIR and CD16A molecules. These
molecules are involved in controlling the effector functions of cyto-
toxic T and NK lymphocytes [12]. It was observed that HLA class I
B*18 allele was significantly less common among herpetic patients,
whereas B35 allele provides protection against HSV-1 [13]. The
severity of primary viral infection with HSV is determined mainly
by the status of the host’s immune response and its interaction with
the attacking viral genes [14]. Establishment of primary HSV infec-
tion is mainly initiated by the Virion host shutoff protein and by
the destruction of complement proteins, natural killer cells, major
histocompatibility complex class I or II molecules and antibodies
of the host immune system [15]. At cellular level, herpes simplex
virus 1 infection affects the metabolism of host cells by dramatically
decreasing the levels of NAD [16].
2.1.1. Role of virion host shutoff protein (vhs)
Virion host shutoff (Vhs) protein is the most important primary
protein that initiates an earliest attack on cellular gene expression.
Vhs is a crucial factor in the pathogenesis, virulence and replication
of HSV. Vhs protein is an endoribonuclease which is encoded by
UL41 gene, is part of the tegument and is synthesized mainly in the
immediate-early and early phases of infection [8,17,18]. Vhs pro-
tein is capable of degrading all types of RNA, but in infected cells vhs
destroys only the mRNA [19,20]. The degradation of cellular mRNA
will decrease the viral competition for cellular translation machin-
ery thus easily establishing and promoting the progression of viral
infection. In contrast, the viral mRNA is highly stabilized by Vhs
through the stabilization of the gE/gI complex which is necessary
for cell-to-cell spread [21]. Vhs reduces the synthesis of innate and
adaptive immune response proteins and thereby blocks the type
I interferon system, dendritic cells and reduces the production of
proinflammatory cytokines and chemokines [22–24] (Fig. 2).
2.1.2. Mechanism of immune evasion
To invade the host immune system and to establish the primary
infection, the herpes simplex virus must overcome all the mucosal
barriers. As a part of evolution, a multitude strategies have been
developed which help HSV to hide from immune evasion [25]. HSV
evades the host immune response by targeting components such as
complement proteins, natural killer cells, major histocompatibility
complex class I or II molecules and antibodies [26]. Glycopro-
tein C binds with C3b and gE binds with the IgG Fc domain thus
blocking complement activation and antibody-dependent cellular
cytotoxicity. HSV expresses the viral gene ICP0, which produces
high resistance to interferon system of the host [27].
2.2. State of latency
Latency is described as a state in viral infection which is charac-
terized as the non-replicating, non-pathogenic, silent persistence
of the virus in the body [28]. It can become active intermit-
tently in presence of certain triggering factors. The sites of latency
vary according to the types of herpes virus. Gammaherpesvirinae
which includes EBV remains latent within the lymphocytes [29].
Betaherpesvirinae including the murine cytomegalovirus estab-
lishes latency in salivary gland cells and in spleen lymphocytes
[30]. Alphaherpesvirinae such as HSV possess a nervous site of
latency especially the trigeminal ganglion whereas other members
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Fig. 2. Establishment of primary infection.
of Alphaherpesvirinae establishes latency within the epithelial cells
[31,32]. Following the establishment of primary infection, HSV-1
enters sensory nerve terminals at the peripheral sites of inoc-
ulation and is transported to the trigeminal nerve ganglion via
retrograde axonal transport. HSV-1 enters into the neuronal cell
by the fusion of the viral envelope with the plasma membrane
rather than through a pH-dependent endocytic pathway [33,34].
This will explain the reason why the capsid proteins are appro-
priate targets to localize viral particles in infected cells. Also, the
establishment of latency within the neuronal cells is contributed
by host factors like neurons, IgG, CD8+ cytotoxic T-lymphocytes
and cytokines and viral factors including down regulation of ␣-
gene expression and DNA replication [35]. The infectious cycle
of HSV-1 within the neuronal cells mainly occurs by the bipha-
sic dynamics of F-actin which will facilitate the efficient infection
and replication [36]. Basically, F-actin is a ATP-bound globular actin
(G-actin) monomers and its assembly is enhanced by the HSV-1
at an early stage of infection to facilitate viral transport [37]. On
the other hand, there will be a decrease in the total cellular F-
actin in favor of viral reproduction, which is observed in the later
stages of infection. This remodeling of actin cytoskeleton is primar-
ily controlled by the actin-depolymerizing factor known as cofilin
[38–40].
2.3. Reactivation of virus and recurrent lesions
HSV will be reactivated from its latent stage by various trigg-
ering factors such as sun exposure, psychological stress, onset of
illness and physical trauma. The reactivated virus then travels from
dorsal root ganglion along the sensory nerves which are located
within the epidermis and at the epidermal-dermal junction. The
virus thus enters the tissues establishing the recurrent infection.
Please cite this article in press as: Kumar SP, et al. Pathogenesis and life cycle of herpes simplex virus infection-stages of primary, latency
and recurrence. J Oral Maxillofac Surg Med Pathol (2016), http://dx.doi.org/10.1016/j.ajoms.2016.01.006
3
Recurrent HSV infection is generally not associated with systemic
signs and symptoms. Recurrent/recrudescent HSV infection mostly
occurs on the mucocutaneous junction of the lip in the form of cold
sores which is also called as recurrent herpes labialis which affects
approximately 16–38% of the population [41]. Intraoral lesions are
rare in recurrent infection and if it occurs, they usually develop
within keratinized mucosa of the hard palate, gingiva and dorsum
of the tongue. Recrudescent lesions are associated with a prodrome
of tingling, itching and burning sensation in 50% of cases. These pro-
drome will be followed by the development of papules, vesicles,
painful ulcers, crusting and then healing of lesions [11].
Lifetime persistence of virus in the body of the host with peri-
odic reactivation is an important characteristic feature of HSV. Viral
shedding may be present even from mucosal surfaces without any
visible lesions. Recurrent lesions highly differ from the primary
lesions in their smaller vesicle size and by the close grouping fea-
ture, and in the usual absence of constitutional symptoms.
2.4. Site specificity for primary and recurrent lesions – role of
keratin
Basically, there are two types of epithelial cells within the oral
cavity-keratinized cells and non-keratinized cells. Keratinized cells
can produce keratin which will then coats the cell surface. Keratini-
zed cells are found in the mucocutaneous junction on the lip, hard
palate, gingiva and dorsum of tongue [6]. Primary lesions of HSV
occur mostly on non-keratinized tissues such as buccal mucosa and
labial mucosa. But primary lesions can also develops on keratinized
tissues like gingiva and the dorsum of tongue [42]. The involve-
ment of both keratinized and non-keratinized tissues of oral cavity
can be explained by the role of keratin coating on the cells. In case
of keratinized cells, strong keratin coat over the cell surface will
prevent the easy penetration of virus into the tissue surface. The
common site of involvement for the primary infections is the non-
keratinized tissues of the oral cavity where the virus likely enters
easily from basolateral surfaces [43]. The lesions on the keratinized
tissues occur only when virus enters through minute breaks in the
keratin coat where the infection starts from the basal layers of the
replicating epithelium.
In contrast to the primary lesions developing on both keratini-
zed and non-keratinized coated tissues, recurrent lesions are highly
restricted to the keratinized epithelial tissues [6]. This site speci-
ficity of the recurrent lesions can be interestingly explained by the
pathogenesis of HSV. The reactivated virus from the dorsal root gan-
glion enters tissues from sensory nerves which are located within
the epidermis and at the epidermal-dermal junction which will be
well below the superficial keratin layer. Thus, in case of recurrent
lesions the virus is already present within the ganglion and then it
travels along the sensory nerves and reaches the tissues. Here the
initial penetration through the cell surface is not required because
the virus is already present within the nerve ganglion after the pri-
mary infection. So the recurrent HSV lesions occur mostly on the
keratinized tissues especially the mucocutaneous junction of lip.
Because in case of recurrent lesions of HSV, keratin has a protective
role which safeguards the virus from immune responses [6].
3. Conclusion
Herpes simplex virus leads a double life: in epithelial cells
HSV performs lytic replication, however in sensory neurons the
virus is able to enter latency and persist indefinitely in this state.
HSV latency is marked by genetic silence, yet upon receiving a
stress stimulus the virus is able to reactivate and replicate to form
infectious progeny. This specialized infectious cycle is the prod-
uct of a complicated interaction between HSV and the neuronal
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environment, which features several levels of regulation. HSV has
evolved to exploit the specific environment of the neuron, a cell
with a distinctive pool of transcription factors and availability of
regulatory mechanisms, to establish a latent reservoir that ulti-
mately fosters the spread and survival of this virus within the
human population. Clinicians should have a clear picture of HSV
pathogenesis, difference in clinical manifestations and specific sites
of primary and recurrent lesions. This will enable them for a timely
diagnosis, management of HSV infections and also helpful in con-
trolling the spread of infection.
Competing interest
Nil.
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