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Genital Herpes: Insights into Sexually Transmitted Infectious Disease



Etiology, transmission and protection: Herpes simplex virus-2 (HSV-2) is a leading cause of sexually transmitted infections with recurring manifestations throughout the lifetime of infected hosts. Currently no effective vaccines or prophylactics exist that provide complete protection or immunity from the virus, which is endemic throughout the world. Pathology/Symptomatology: Primary and recurrent infections result in lesions and inflammation around the genital area and the latter accounts for majority of genital herpes instances. Immunocompromised patients including neonates are susceptible to additional systemic infections including debilitating consequences of nervous system inflammation. Epidemiology, incidence and prevalence: More than 500 million people are infected worldwide and most reported cases involve the age groups between 16-40 years, which coincides with an increase in sexual activity among this age group. While these numbers are an estimate, the actual numbers may be underestimated as many people are asymptomatic or do not report the symptoms. Treatment and curability: Currently prescribed medications, mostly nucleoside analogs, only reduce the symptoms caused by an active infection, but do not eliminate the virus or reduce latency. Therefore, no cure exists against genital herpes and infected patients suffer from periodic recurrences of disease symptoms for their entire lives. Molecular mechanisms of infection: The last few decades have generated many new advances in our understanding of the mechanisms that drive HSV infection. The viral entry receptors such as nectin-1 and HVEM have been identified, cytoskeletal signaling and membrane structures such as filopodia have been directly implicated in viral entry, host motor proteins and their viral ligands have been shown to facilitate capsid transport and many host and HSV proteins have been identified that help with viral replication and pathogenesis. New understanding has emerged on the role of autophagy and other innate immune mechanisms that are subverted to enhance HSV pathogenesis. This review summarizes our current understanding of HSV-2 and associated diseases and available or upcoming new treatments.
| 438 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
ABSTRACT Etiology, transmission and protection: Herpes simplex virus-2
(HSV-2) is a leading cause of sexually transmitted infections with recurring
manifestations throughout the lifetime of infected hosts. Currently no effec-
tive vaccines or prophylactics exist that provide complete protection or im-
munity from the virus, which is endemic throughout the world. Patholo-
gy/Symptomatology: Primary and recurrent infections result in lesions and
inflammation around the genital area and the latter accounts for majority of
genital herpes instances. Immunocompromised patients including neonates
are susceptible to additional systemic infections including debilitating conse-
quences of nervous system inflammation. Epidemiology, incidence and preva-
lence: More than 500 million people are infected worldwide and most report-
ed cases involve the age groups between 16-40 years, which coincides with an
increase in sexual activity among this age group. While these numbers are an
estimate, the actual numbers may be underestimated as many people are
asymptomatic or do not report the symptoms. Treatment and curability: Cur-
rently prescribed medications, mostly nucleoside analogs, only reduce the
symptoms caused by an active infection, but do not eliminate the virus or
reduce latency. Therefore, no cure exists against genital herpes and infected
patients suffer from periodic recurrences of disease symptoms for their entire
lives. Molecular mechanisms of infection: The last few decades have generat-
ed many new advances in our understanding of the mechanisms that drive
HSV infection. The viral entry receptors such as nectin-1 and HVEM have been
identified, cytoskeletal signaling and membrane structures such as filopodia
have been directly implicated in viral entry, host motor proteins and their
viral ligands have been shown to facilitate capsid transport and many host
and HSV proteins have been identified that help with viral replication and
pathogenesis. New understanding has emerged on the role of autophagy and
other innate immune mechanisms that are subverted to enhance HSV patho-
genesis. This review summarizes our current understanding of HSV-2 and as-
sociated diseases and available or upcoming new treatments.
Genital Herpes: Insights into Sexually Transmitted
Infectious Disease
Dinesh Jaishankar
and Deepak Shukla
Departments of Bioengineering and Ophthalmology and Visual Sciences, University of Illinois at Chicago, IL 60612.
Department of Microbiology and Immunology, University of Illinois at Chicago, IL 60612.
Department of Pathology, University of Illinois at Chicago, IL 60612.
* Corresponding Author:
Deepak Shukla, E-mail:
Genital herpes is one of the most common, persistent and
highly infectious sexually transmitted viral infections most-
ly caused by herpes simplex virus-2 (HSV-2) and in many
emerging first time cases, by HSV-1 [1]. Primary and recur-
rent genital herpes infections most commonly result in
lesions and inflammation around the genital area. In wom-
en, the sites of infection are mainly the vulva and the vagi-
na, with some cases involving the regions of cervix and
perianal. In heterosexual men infection is typically on the
glans or the shaft of the penis, whereas anal infection is
also reported with homosexual men. More than 500 mil-
lion people are infected worldwide and most cases report-
ed are among the age groups between 16-40 years that
doi: 10.15698/mic2016.09.528
Received originally: 09.11.2015;
in revised form: 24.12.2015,
Accepted 07.01.2016,
Published 27.06.2016.
Keywords: herpes simplex virus, virus
entry, viral glycoproteins, viral latency,
3-OST – 3-O-sulfotransferase,
g – glycoprotein,
HPSE - Heparanase
HS – heparan sulfate
HSPG – heparan sulfate proteoglycan,
ICP – infected cell protein,
LAT – latency associated transcripts,
NMIIA – non-muscle myosin II A
PILRα paired immunoglobulin-like
type 2 receptor α;
D. Jaishankar and D.Shukla (2016) Genital Herpes and STI
| 439 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
coincides with increased sexual activity among this age
group [2]. While these numbers are an estimate, the actual
numbers may be underestimated as many people are ei-
ther asymptomatic or are unaware of the infection [3]. This
review provides an insight into the epidemiology, patholo-
gy, our current understanding of the molecular mecha-
nisms of infection and the currently available and upcom-
ing treatments for genital herpes.
Herpesviruses are among the most ubiquitous of human
infections. After infection with HSV, it is thought that the
virus and the immune response to the virus persist through
the life of the host. HSV infections are measured by testing
various populations for the presence of antibodies specific
to the virus. An estimated 90% of all people worldwide
have one or both viruses [4, 5]. HSV-1 is the more preva-
lent virus with 65% of persons in the United States having
antibodies to HSV-1 [6], while HSV-2 infections are marked-
ly less frequent, with 15%–80% of people in various popu-
lations infected [7]. HSV-1 and HSV-2 infection rates widely
vary between countries. The increase in genital HSV-1 is
mainly attributed to an increase in oral sex among young-
sters and adults which is viewed safer than intercourse [8].
Due to this, in the USA, Canada, and other European coun-
tries, at least half of the first episodes for genital herpes
have been caused by HSV-1 in the past decade [9-12]. In a
study performed by the CDC it is estimated that about one
in six Americans aged 14 to 49 are infected with HSV-2 and
the prevalence in women was 20.9%, twice as high as
among men [13]. While a surge of HSV-2 seroprevalence
from 16.4% to 21.8% was observed from 1976 to 1994 [14],
this trend has reversed, dropping to 17.2% in 2004 [15]. In
Africa and other developing countries, there is a high bur-
den of HSV-2 infections with >50% prevalence in the popu-
lation [16]. Around 82% of women and 53% of men in the
Sub-Saharan Africa are seropositive for HSV-2 [17]. HSV-2
infection rates also depend on the rates of sexual activity
and are more prevalent in heavily exposed populations,
such as commercial sex workers, who are nearly 100% pos-
itive, suggesting an urgent need for education and new
measures for prevention [18].
HSV are linear, double stranded DNA viruses capable of
establishing latency in humans. They belong to the family
of Herpesviridae and more specifically to the sub-family of
Alphaherpesvirinae. There are two sub-types: HSV-1 and
HSV-2 that are closely related but differ slightly in tissue
tropism and antigenic properties. The viral DNA is present
in the core that is enclosed in a protein shell called the
capsid (Fig. 1). The icosahedral shaped capsid is
125 nm
in diameter, which is connected to and surrounded by a
glycoprotein expressing lipid bilayer membrane envelope
via a protein coat called the tegument. The viral envelope
contains at least 12 glycoproteins many of which play ma-
jor roles in the entry and egress of the virus. A list of HSV
glycoproteins along with their reported functions is provid-
ed in Table 1.
2 lytic infe
tion. The HSV-1/HSV-2 virion recognizes and
attaches to the heparan sulfate proteoglycan via
glycoproteins on the viral envelope. By a process
called ‘surfing’, the virus particles can travel
along filopodia-like membrane extensions to
reach the surface of the cell. On the surface of
the cell, viral capsid penetration can occur by
fusion of envelop with the plasma membrane (I),
or alternatively by endocytosis of enveloped
virions with eventual fusion of the envelope with
a vesicular membrane (II). In either case, gD on
the virus envelope is required via its interaction
with one of the receptors (shown in red): her-
pesvirus entry mediator (HVEM) or nectin-1 and-
2. In the cytoplasm, the capsid (brown) travels to
the nucleus where the viral DNA is released.
Multiple rounds of replication result in multiple
copies of viral DNA and other components that
get packaged and assembled in the nucleus.
During egress, the newly assembled capsid gets
its primary envelope at the peri-nuclear mem-
brane, which is lost during egress from the outer
nuclear membrane. Naked capsid travels
through the cytoplasm where it receives the
tegument and the viral envelope (presumably
from the Golgi or the ER). Heparanase (denoted
as pink spots) is an enzyme that was recently
described in aiding viral egress. The enzyme cleaves of cell surface heparan sulfate (dotted black) which clears the path for the virus to exit
the cell.
D. Jaishankar and D.Shukla (2016) Genital Herpes and STI
| 440 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
List of HSV glycoproteins and their reported functions.
Glycoprotein Function References
gB Fusogenic protein: class III [23]
gC Attachment and C3b receptor [20, 24]
gD Virus entry and fusion [19, 21]
gE Virus spread and Fc receptor [22, 25]
gH Virus entry and fusion [19, 21]
gI Virus spread and Fc receptor [22, 26, 27]
gK Virus spread and egress [28, 29]
gL Viral entry and fusion [19, 24]
gM Virus assembly and fusion [30-32]
The lifecycle of HSV has been mostly studied and char-
acterized using HSV-1 infections. However, HSV-2 infec-
tions are considered similar to HSV-1 infections. Different
stages in the HSV lifecycle can be broadly classified into:
i. Attachment: Initiation of infection begins with the at-
tachment of viral glycoproteins to the cell surface. Heparan
sulfate proteoglycans (HSPGs) on the cells serve as attach-
ment sites for HSV [19]. Glycoproteins B and C (gB and gC)
on the HSV envelop bind to the HSPGs and are essential to
initiate attachment. A study by Herold et al., using a gB and
gC null virus showed reduction in the overall virus attach-
ment to the cells as well as reduction in virus infectivity
[20]. Moreover, it has been shown that in the absence of
gC gB can take over and help in attachment to cells, indi-
cating a gC-independent mode of viral attachment [33].
HSV was shown to bind to HS (heparan sulfate) on the filo-
podia, which are plasma membrane protrusions, and use
filopodial interaction to migrate towards the cell body to
initiate entry. This process was termed “viral surfing” [34].
In this study, viral particles were shown to surf along the
filopodia and the formation of filopodial structures in-
creased upon HSV infection, possibly due to activation of
Rho GTPase signaling during virus attachment to cells. Flu-
orescence imaging revealed that HSPG expression is higher
along the filopodial structures. This mode of attachment
has also been reported for vaccinia virus, human papilloma
virus type 16, hepatitis C virus, and human immunodefi-
ciency virus (HIV) [35].
ii. Entry: After the initial attachment to the cell surface,
virus entry is the next step in the lifecycle. Various modes
of viral entry have been established. The virus is taken into
the cells by either direct fusion with the plasma membrane,
which is independent of pH change, or through endocytosis
mediated by specific cellular receptors. The glycoprotein D
(gD) on HSV plays an important role in both of the afore-
mentioned uptake processes and glycoproteins H and L (gH
and gL) act in concert to complete the fusion machinery. To
date the following receptors have been identified for gD:
herpes virus entry mediator (HVEM), nectin-1 and -2 and 3-
O sulfated heparan sulfate (3-OS HS) [21]. HVEM was the
first identified HSV receptor that belongs to the tumor ne-
crosis factor (TNF) superfamily. The next set of receptors
identified is represented by nectin-1 and -2. They belong to
the immunoglobulin superfamily. The last receptor is a rare
modification of the large sugar molecule HS mediated by
the 3-O-sulfotransferase 3 (3-OST-3). 3-OST-3 belongs to
the family of 3-O sulfotransferases (3-OSTs) that place sul-
fate groups at the 3-OH position on the glucosamine in HS.
This specific and rare modification of HS dictates the bio-
logical activity of HS and occurs during the last step of HS
biosynthesis. As an example, modification of HS by 3-OST-1
serves as a binding site for antithrombin, a major player in
anticoagulation [36]. 3-OST-3 modified HS serves as an
entry receptor for HSV and addition of soluble form of 3-OS
HS in HSV resistant cell lines showed increased viral entry
[38, 39]. Interestingly, 3-OST-3 generated receptor fails to
mediate HSV-2 entry but may probably help in the attach-
ment of HSV-2 [19, 38].
Viral entry can occur in the presence of any one of the
aforementioned receptors and absence of all three recep-
tors abolishes viral entry. Even though gD is needed for
receptor-mediated endocytosis and also for the direct fu-
sion of viral envelop to the plasma membrane, there seems
to be no clear consensus on how and which mode of entry
the viruses use in human hosts or animal models. While
entry into some cultured cells like CHO, HeLa and HCEs are
reported to be through receptor mediated endocytosis,
entry into Vero and neuronal cell lines are through direct
fusion with the plasma membrane [39, 40]. In addition to
gD playing a vital role in viral entry, accumulating evidence
also suggests the important role of gB in HSV entry as a gB
null virus was unable to enter and cause infection in target
cells [41]. Paired immunoglobulin-like type 2 receptor α
(PILRα) has been shown to associate with gB to function as
a co-receptor in aiding HSV-1 entry. Mutations on the sites
where gB attaches to PILRα not only reduced viral entry
but also reduced viral replication and neuroinvasiveness
[42-44]. Furthermore, another protein that belongs to the
sialic acid-binding Ig-like lectin family which shares a simi-
lar homology to PILRα called the myelin-associated glyco-
protein (MAG) acts as a co-receptor for HSV-1 entry when
expressed exogenously [45]. Another co-receptor called
non-muscle myosin IIA (NMIIA) was also identified to bind
gB on the cell surface and aide in the viral entry [46]. As an
actin binding motor protein, NM-IIA plays a critical role in
cell adhesion and migration. The glycoproteins gH and gL
together with gB and gD form the fusion complex [47, 48].
gH exists as a hetero-oligomeric complex with gL. This
D. Jaishankar and D.Shukla (2016) Genital Herpes and STI
| 441 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
complex is essential for the processing and cell surface
expression of gH [49, 50] and is conserved in many of the
herpesviruses [51]. Apart from playing a role in the fusion
machinery, the gH/gL complex plays a role in virus entry by
interacting with various cell surface proteins [52], integrins
being the most common. Interaction of gH with integrin
αvβ3 facilitates HSV-2 viral entry and calcium signaling in
human genital tract epithelial cells [53]. Another study
shows that αvβ6 and αvβ8 serve as interchangeable recep-
tors for gH/gL that promote endocytosis and activation of
membrane fusion [54]. A recent study by the same group
also found that conformational changes in the above men-
tioned integrin receptors are essential to promote the dis-
sociation of gL from the gH/gL complex, a proposed new
mechanism in HSV viral entry [55].
Other alternative modes of viral entry have also been
identified. A phagocytosis-like uptake of the virus particles
was reported to be observed once the virus particles have
attached to the filopodia; it is believed to exhibit mixed
traits of endocytosis and phagocytosis [56]. Cytoskeleton
rearrangement and their associated cellular signaling
pathways have also been implicated in facilitating HSV en-
try into cells [57]. Rho-GTPase signaling pathway involving
Rho-A and cdc42, key modulators in the formation of filo-
podia, were shown to be activated and aide in the phago-
cytic-like uptake of the virus [56]. Another signaling path-
way called phosphoinositide 3 kinase (PI3K) pathway,
which is involved in the downstream of the filopodial for-
mation, was also found to affect multiple steps in the HSV
entry [58]. This same pathway is also implicated to control
the activity of cofilin, a family of actin-binding proteins, in
facilitating entry of virus into neuronal cells [59]. The acti-
vation of Akt signaling in triggering calcium release which
aids in HSV viral entry has also been shown [60].
iii. Capsid Transport and Replication: Upon successful
entry into cells, the viral capsid and tegument proteins are
released into the cytoplasm. The virion host shutoff protein
(vhs) is a viral tegument protein that is released into the
cytoplasm after entry and degrades host mRNAs that regu-
late stress response. The capsid then translocates to the
nucleus along microtubules via the dynein and dynactin
motor proteins and releases the viral DNA into the nucleo-
plasm [61-63]. A recent study reported the role of heat-
shock protein 90 (Hsp90) to be involved with HSV capsid
transport to the nucleus via interaction with acetylated α-
tubulin [64]. The uncoating of viral DNA occurs at the nu-
clear pore.
iv. Replication and Assembly: Once inside the nucleus,
several viral genes are expressed in an ordered fashion.
The proteins of the α genes or intermediate early (IE)
genes are the first to be transcribed. The products of these
genes are termed as infected cell protein (ICP) and there
are five ICPs: 0, 4, 22, 27 and 47. The virus encodes a teg-
ument protein: VP16 that aids in the transcription of the α
genes. The expression of ICP4 is then thought to drive the
expression of the β genes or the early genes. The β genes
encode for various proteins that promote viral DNA repli-
cation, including the enzyme thymidine kinase (TK). The
virus utilizes TK for replication leading to the expression of
the γ or late genes. The proteins of the γ genes encode for
several components of the viral structure including capsid
and envelop proteins. Various viral components are
formed which then assemble and the viral DNA is repack-
aged into a new capsid. Fully assembled capsid exits from
the nucleus by acquiring a glycoprotein-containing envelop
at the inner nuclear membrane and losing it at the outer
membrane when the naked capsid is released in the cyto-
plasm for re-envelopment using a Golgi-derived membrane
(Fig. 1).
v. Autophagy Modulation during Active Replication:
The role of autophagy, a cellular process involved in main-
taining the metabolic and homeostatic activity, in HSV rep-
lication has been widely studied. The ICP34.5 protein, a
neurovirulence factor, regulates the replication of HSV by
controlling the autophagic pathway via inhibition of either
PKR/eIF2a signaling pathway [65, 66] or beclin-1, a protein
involved in the formation of autophagosomes [67]. A re-
cent study showed that a basal level of autophagy is need-
ed for efficient replication of virus and disrupting the basal
level would lead to reduced viral titers [68]. Another recent
study showed the role of a host cytoplasmic protein called
axin in controlling autophagy and HSV replication [69]. The
results from this study indicate that axin expression reduc-
es the levels of cellular autophagy induced by HSV, result-
ing in enhanced HSV replication.
vi. Latency and Reactivation: One of the key traits of
this family of viruses is to go latent for the life of the host
after primary infection. How and why the virus goes latent
is only partially understood and is one of the hot topics in
herpes research. After a lytic infection the virus has the
ability to evade and mask itself from the host defense.
Latency is established when the virus migrates to the sen-
sory ganglia via a retrograde fashion and invades the nu-
cleus of the neurons (Fig. 2). In the nucleus the HSV ge-
nome is maintained in a circular form and remains in a
silent state. During this state, a region of the genome that
encodes for the latency associated transcripts (LATs) re-
mains active [70]. Kramer et al. also showed the presence
of HSV transcripts using RT-PCR analyses in latently infect-
ed mouse ganglia [71, 72]. The exact role and function of
the LATs also remains to be completely understood. How-
ever, research over the last decade has revealed the com-
mon functions of LAT: they help in reducing the expression
of the viral genome thereby maintaining them in a latent
state protected from the immune system [73] and they
protect infected neurons from apoptosis, thus increasing
the amount of latent transcripts that would eventually
increase the viral load upon reactivation [74, 75]. In addi-
tion, the host immune system has also been implicated to
play a vital role in viral latency. Studies in the mouse mod-
els of latent HSV infection revealed the presence of infil-
trating immune cells and cytokines in latently infected gan-
glia [76-78] while some suggest that the presence of low
viral transcript levels could lead to a local milieu of immune
effectors that could repress HSV gene expression [79, 80].
Some evidence also suggests the role of neuronal functio in
maintaining latency [81-83]. Furthermore, during latent
infection, the ability of some parts of the HSV genome to
D. Jaishankar and D.Shukla (2016) Genital Herpes and STI
| 442 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
remain transcriptionally active and inactive suggested the
presence of epigenetic control. Two studies that used
computational analysis and latently infected mice revealed
that DNA methylation, a most common epigenetic mecha-
nism, did not regulate HSV latent gene expression [84, 85],
leading to the investigation of other epigenetic mecha-
The role of chromatin and HSV latency has gained in-
creasing popularity as the HSV DNA is devoid of histones
[86] but upon infection gets assembled into the nucleo-
some [87] and associates with histones [88]. However
whether heterochromatin or euchromatin play a role in
HSV latency was not known. Only recently, using various
molecular techniques, the presence of heterochromatin or
euchromatin in HSV-infected cells has been studied to pro-
vide a basis for a chromatin-based epigenetic mechanism
of HSV gene regulation in different cell types [89]. In a
study by Kubat et al., their findings showed that active
chromatin was associated with LAT gene as increasing lev-
els of acetylated H3 histone were found to be associated
with the LAT promoter and enhancer compared with the
ICP0 gene [90]. In another study by Wang et al., it was
shown that as latent infection is established the HSV lytic
genes are progressively associated with chromatin that
contains dimethylation of H3K9me2, which is an indicator
of heterochromatin [91]. Thus there is a general notion
that during latent infection the LAT gene is associated with
euchromatin whereas the lytic genes are associated with
heterochromatin. The study by Amelio et al. gave insights
into how and why different chromatin are maintained and
regulated separately on the latent viral genome [92]. Their
study identified candidate insulator elements, DNA se-
quences that bind protein factors that maintain chromatin
boundaries. These contain CCCTC sites that are bound by
the CCCTC-binding factor (CTCF) upstream of the LAT pro-
moter boundary and in the LAT intron. They proposed that
insulators keep the LAT euchromatin activity within a
boundary and heterochromatin outside of the same
Reactivation of the latent virus occurs when an external
stimuli or ‘stress’ is applied to the neuron. Various factors
such as environmental conditions, fever, exposure to sun-
light and other unknown conditions have been attributed
to cause reactivation but their exact targets at the molecu-
lar level remain unknown. When the virus reactivates it
travels from the sensory ganglia via anti-retrograde fashion
to the primary infection site or sites of high neuron inner-
vations where active virus replication and shedding occur
and symptoms like pain, inflammation and lesions develop.
In an effort to understand the exact role of LATs in the
Figure 2: Schematic of Primary Infection and Reactivation. Primary infection occurs when a host is exposed to the virus for the first time.
When a person is exposed to HSV, the virus infects the epithelial cells. Depending on the immune system of the host, lytic infection leads to
virus shedding that can cause symptoms such as ulcers or remain asymptomatic. After lytic infection, the virions reach the nerve endings
and through a retrograde transport, reach the sacral ganglion where it establishes latency till the life of the host. Recurrent infections occur
when the virus gets reactivated due to stress, environmental conditions and other unknown factors. Reactivation causes the virus from the
sacral ganglion to travel to the site of primary infection or high nerve endings via an anterograde fashion where virus shedding can cause
symptoms or remain asymptomatic depending on the host immune system.
D. Jaishankar and D.Shukla (2016) Genital Herpes and STI
| 443 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
reactivation of HSV, LAT encoded micro RNAs (miRNA)
were discovered. miRNAs are a family of non-coding RNA
that is approximately 22 nucleotides in length. They usually
function at a post-transcription level by inhibiting protein
synthesis via mRNA degradation. HSV miRNAs have been
shown to be expressed during productive infection, which
helps degrade host immune responses as well as during
latency, which helps in establishing latency or helps in re-
activation [93].
vii. Egress: Upon formation of capsid and packaging of
the virus DNA, the virions eventually have to egress or
leave the nucleus and the cell to get into the extracellular
environment. While the process of HSV egress still requires
some clarity due to varying experimental models and com-
plexity in studying the virus-nuclear interactions, the fol-
lowing is the accepted model for viral egress. Budding is
the initial step in the nuclear egress of HSV. In this process
the capsid acquires the envelope from the inner nuclear
membrane and two viral proteins: UL31 and UL34 are re-
ported to be necessary for the budding process [94]. Once
the virus reaches the perinuclear region, it is thought to
lose the primary envelope or undergoes de-envelopment
and evidence suggests that the final assembly of tegument,
envelope and the glycoproteins occur within the cytoplas-
mic compartments (presumably in the Golgi or Endoplas-
mic Reticulum, ER). During productive infection either in
primary infection or after reactivation, for efficient trans-
mission and infection, the virus needs to spread to neigh-
boring cells. The release of the virus from infected cells
requires both host factors and viral components. Among
the viral components, glycoproteins E and I (gE and gI) are
needed for efficient spread of viruses in certain polarized
and non-polarized epithelial cells and neuronal cells [95,
22]. Among the host factors, a HS degrading enzyme: hepa-
ranase (HPSE) has been recently shown to aide in viral
egress [96]. The study shows how the levels of HPSE in-
crease over time with HSV infection as active form of HPSE
is translocated to the plasma membrane of infected cells to
remove HS for smoother release of newly generated viri-
ons. The role of myosin motor proteins such as NMIIA and
myoVa have also been implicated in HSV egress [97, 98].
Genital herpes is predominantly transmitted through
sexual contact. Viral transmission by oro-genital contact is
mostly HSV-1 and therefore the number of genital HSV-1
cases is on the rise [99-101]. Virus shedding is more pre-
dominant in sites like mouth and mucosal surfaces such as
the vagina. Contact with any one of these increases the risk
of being infected with HSV.
An episode or outbreak is termed as the phase in which
individuals experience symptoms and the severity of these
episodes depends on previous immunity to HSV. Notably,
almost 25% of people presenting with a first clinical epi-
sode of genital herpes have serological evidence of past
HSV-2 infection at the time of presentation, suggesting
initial infection was asymptomatic [102]. In many other
instances of primary infections where the patient encoun-
ters HSV for the first time the first episode may occur any-
where between 2 days to 2 weeks after primary infection.
Primary infections are clinically most severe and most likely
symptomatic [103]. Symptoms like fever, itching and mus-
cle pains usually in the lower part of the body are most
common in primary infection; 40% of men and 70% of
women also report fever, headache, malaise, and myalgias
[104]. Papule formulation followed by a wide distribution
of blisters or lesions appear around the genital areas that
eventually break to form ulcers (Fig. 2). Over a period of
time the ulcers crust and heal. In women common sites for
lesion are the cervix, vagina, labia majora and minora and
perianal region through infected vaginal fluid and in men it
is mostly on the shaft or the glans of the penis. Anal lesions
are also reported in homosexual men. Primary infections
either by HSV-1 or by HSV-2 cannot be differentiated just
by clinical symptoms; additional laboratory testing is need-
ed to differentiate between the two viruses.
At the tissue and molecular level, HSV-2 infects the epi-
thelial cells on the genital mucosa leading to an increase in
inflammatory response and cell death at the site of infec-
tion. Multinucleated cells and syncytia formation are the
most common observation in cells infected with HSV. The
recruitment of macrophages, natural killer cells, B-cell and
T-cell mediated immunity [105, 106] and the release of
cytokines has been reported to play a role in innate and
adaptive immunity to HSV infections. This contributes to a
chronic inflammatory state in genital skin and mucosa.
Histopathologic studies of foreskin in HIV-seronegative
men after adult circumcision have shown a higher concen-
tration of CD4
and CD8
T-cells in HSV-2–seropositive
compared with HSV-2–seronegative men [107]. During the
course of primary infection, the virus spreads via a retro-
grade fashion along the microtubules lining the axons to
the dorsal root ganglia (DRG) where the neuronal cells act
as reservoirs for the virus to remain latent [108]. Upon
reactivation due to factors such as stress and other un-
known conditions, the virus spreads from the DRG to the
epithelial cells via an anterograde fashion where a lytic
replication of the virus follows, resulting in virus shedding.
This is the cause of recurrent infections and these infec-
tions are usually asymptomatic or may be associated with a
classic genital ulcer. While the innate immune system, spe-
cifically the CD8
T-cells and the plasmacytoid dendritic
cells, are attributed in controlling latency and reactivation
of the virus [80, 109, 110], recent reports suggest other-
wise. Studies have shown that CD8α dendritic cells help
drive the establishment of HSV-1 latency [111, 112]. At a
clinical and subclinical level, the severity of viral reactiva-
tion varies widely from person to person and depends on
cell mediated immunity that is considered important for
control of viral replication [113, 114].
Diagnosis of genital herpes based purely on clinical presen-
tation is often not accurate and could be misleading. Symp-
toms occurring from other bacterial infections like Trepo-
nema pallidum or Haemphilus ducreyi could be confused
D. Jaishankar and D.Shukla (2016) Genital Herpes and STI
| 444 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
with HSV resulting in wrong diagnosis [115]. Genital herpes
may also cause atypical symptoms that occur at unusual
sites such as the thighs or the buttocks. HSV-2 is also found
to be a co-factor for HIV-1, which is one of the leading
causes of sexually transmitted infections and at times it
becomes difficult to diagnose the symptoms that occur due
to HIV-1 co-infections [116]. Hence, along with clinical di-
agnosis, laboratory tests are required to accurately diag-
nose genital herpes. To determine the presence of HSV in
laboratory, swabs from the genital lesions are taken and
tested by the following common techniques:
i. Viral culture of HSV has been a gold standard for la-
boratory diagnosis of HSV for the past two decades. Using
the swabs from the genital lesions, the virus can be grown
on tissue culture, usually within 5 days, that is then detect-
ed using immunofluorescence assays or by enzyme immu-
noassay. The limitation with this method is that it lacks
sensitivity as more viruses are usually obtained from pa-
tients with primary infection (80%) but less from patients
with recurrent infections (20-50%) or patients whose le-
sions have begun to heal [117].
ii. Polymerase Chain Reaction (PCR): This method of
nucleic acid amplification has emerged as the next com-
mon method to assess the presence of HSV. Determining
HSV by PCR is faster and four times more sensitive com-
pared to viral culture [118, 119]. Based on this method,
three assays have been approved by the US Food and Drug
Association for the detection of HSV in genital lesions. The-
se include IsoAmp HSV Assay, BioHelix Corporation; Multi-
Code-RTx Herpes Simplex Virus 1 & 2 Kit, EraGen Biosci-
ences, Inc. and BD ProbeTec Herpes Simplex Viruses (HSV I
& 2) QX Amplified DNA Assays, BD Diagnostic Systems.
With increasing technology and advances in kit develop-
ments for HSV detection and typing using PCR, this method
is rapidly replacing the viral culture assay.
iii. Serotyping: This method can not only be used to
detect the presence of HSV but can also be used to
differentiate between genital herpes originating from HSV-
1 or HSV-2. Type-specific IgG against the glycoprotein G
(gG) of HSV-1 and HSV-2 are available that can be used to
distinguish between the two viruses [120]. Serotyping has
another advantage in that it detects the presence of HSV to
confirm if the infection is a primary or recurrent infection.
In primary infection, type-specific HSV antibodies can take
from 2 weeks to 3 months to develop. Therefore, an initial
absence of IgG antibodies specific for gG and subsequent
development of such antibodies after 12 weeks confirms
new HSV infection. Clinicians also recommend this method
to diagnose genital herpes when there are no lesions or
the above mentioned detection tests do not provide
substantial results.
While this review only mentions the above common
techniques to diagnose genital herpes in a laboratory
setting, there are currently other methods and techniques
being developed by research institutes and companies. For
example, LeGoff et al. provide a detailed description of
other available and upcoming diagnostic methods [121].
Genital herpes conditions are primarily treated with antivi-
rals that aim at controlling viral replication. Acyclovir, its
analogue Valacyclovir and Famcyclovir (prodrug of Pency-
clovir) are currently prescribed for genital herpes treat-
ment. These drugs are nucleoside analogues that specifi-
cally inhibit the herpesvirus DNA polymerase. While cyclo-
vir is available in oral and intravenous formulations,
Valacyclovir and Famcyclovir are available only as oral for-
mulations. For primary infections where the symptoms can
be severe, antiviral therapy is usually started even before
the symptoms are confirmed by laboratory diagnosis and
the duration of the therapy is 7-10 days or till the lesions
are healed [122]. In severe cases, to relieve pain, clinicians
recommend the use of analgesics or sitz baths where the
patients’ hips and buttocks are immersed in lukewarm
water [117].
Preventive strategies to efficiently reduce the transmis-
sion of the virus also exist and in combination with the
above mentioned treatments there could probably be a
significant reduction of viral transmission. In the case of
people that have symptomatic viral shedding, the most
common preventive strategy is to abstain from sexual ac-
tivity or to use condoms. A prospective study showed sig-
nificantly lowered levels of viral acquisition among part-
ners that used male condoms [123]. Although it is thought
that female condoms can also reduce virus transmission,
this has not been clinically investigated. Applications of
topical microbicides to prevent genital herpes infections
are also being investigated. This strategy involves the use
of natural or synthetic products that either increase the
natural vaginal defenses or inactivate the HSV virions [124,
125]. A recent study showed that vaginal application of
tenofovir gel, an antiviral microbicide which functions as a
nucleotide reverse-transcriptase inhibitor, reduced the
levels of HSV-2 acquisition among women in South Africa
Various other therapeutic and prevention strategies
that target different stages of virus lifecycle are currently
being investigated. Peptide therapeutics is fast rising owing
to the ease of synthesis, modifications and their high speci-
ficity [126]. They are being synthesized and used as inhibi-
tors against HSV infections [127]. The TAT (transactivator
of transcription)-peptide, derived from HIV, has been
shown to inhibit infection of HSV in the in vitro and in vivo
models of HSV infections [128, 129]. A study showed the
effect of a synthetic 3-OS HS specific peptide: G2 in block-
ing HSV-2 infections in human cervical (HeLa) cell lines. This
peptide significantly blocked the entry and thereby the
spread of the virus [130] and a D-enantiomer of this pep-
tide exhibits higher stability and more promise in inhibiting
HSV infection [131]. Another study designed synthetic pep-
tides specific to the glycoproteins gD and gG and showed
that these peptides can effectively recognize HSV-2 anti-
bodies and hence may be used for serodiagnostic assays
[132]. Because HSV utilizes the cytoskeleton filaments and
kinases during its entry, a recent study showed that block-
ing the myosin light chain kinase (MLCK) with inhibitors
D. Jaishankar and D.Shukla (2016) Genital Herpes and STI
| 445 Microbial Cell | SEPTEMBER 2016 | Vol. 3 No. 9
such as blebbistatin significantly reduces HSV infection
[133], providing new evidence for potential targets in
blocking HSV infections. The advent of nanoparticles in
drug delivery was successful, owing to their ability to pro-
vide sustained or extended delivery of drugs at a local site.
Nanoparticles or nanoparticle compositions to protect
against HSV-2 infections are also being actively researched.
Zinc Oxide (ZnO) nanoparticles exhibited significant antivi-
ral activity in both the in vitro model using vaginal epitheli-
al cells and the in vivo mice model of HSV-2 infections
[134]. Three different modes of treatment were used in
this study: prophylaxis, therapeutic and neutralization. In
all the three modes of treatment, the ZnO nanoparticles
showed promising results in blocking HSV-2 infections.
Another study showed the potential antiviral use of mucus-
penetrating nanoparticles [135]. In this study, acyclovir
monophosphate loaded mucus-penetrating nanoparticles
showed an increase in drug retention and distribution
thereby providing an effective protection against HSV-2
Protection against genital herpes infections can be en-
hanced by induction of protective immune responses using
vaccines. Vaccines against genital herpes are underway
and in the majority of clinical trials only prophylactic vac-
cines have seen success so far. There have been no reports
of any therapeutic vaccines that show promise against
genital herpes infections. These vaccines consist of subu-
nits of glycoproteins such as gD or gB. A gD2 subunit vac-
cine, when administered with alum as adjuvant, showed
around 39-46% efficacy in preventing HSV-2 infections in
patients that were seronegative for HSV-1 and HSV-2 but
did not provide protection to patients that were seroposi-
tive for HSV-1 [136, 137]. Other viral glycoproteins such as
gC and gE are also being used as vaccines to study their
effectivity in blocking genital herpes infections [138, 139].
Peptide based vaccines are also being developed to incite
immune responses against HSV-2 infections. A study de-
veloped a peptide based vaccine: HerpV, which generates
and CD8
responses when subjected to HSV-2 chal-
lenge [140, 141].
There is no doubt that our understanding of HSV-2 lifecycle
and associated pathogenesis has improved dramatically
over the last several years but challenges remain in many
areas, especially those relating to disease management
and prevention. The new knowledge has provided a major
opportunity to develop new strategies for patient care by
combining our understanding of viral infection mechanisms,
host immune responses, and the viral mechanisms that
subvert them. New anti-HSV drugs are on the horizon,
many of which may target other herpesviruses as well. At
present, the development of vaccines against HSV-2 is a
highly active area of research and many innovative
strategies are currently being tested for an effective
vaccine generation. Future clinical trials will see many new,
non-nucleoside anti-herpetic drug candidates as well as
many newer approaches, including immune-based
therapeutics. An area that needs extra attention is rapid
diagnostics, especially since genital herpes can be caused
by both HSV-1 and HSV-2. Therefore quick and easily
available tests can yield much better results in reducing
symptoms and lowering transmission rate. Any success in
reducing transmission rate will mean a step closer to the
greatest challenge for herpes virologists, which is complete
elimination of this lifelong infection.
This work is supported by a NIH grant (AI103754) to D.S.
The authors declare no conflict of interest.
© 2016 Jaishankar and Shukla. This is an open-access arti-
cle released under the terms of the Creative Commons
Attribution (CC BY) license, which allows the unrestricted
use, distribution, and reproduction in any medium, provid-
ed the original author and source are acknowledged.
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... HSV-1 is the most common cause of oro-labial infections. These infections are most commonly acquired through direct physical contact during childhood (19). HSV-1 infection affects an estimated 3.7 billion people under the age of 50 (67%) worldwide (20). ...
... The study instrument consists of two parts: Part I Demographic Characteristics include age, level of education, years of experience, training courses in TORCH diseases, and source of information. Part II of nurse-midwives knowledge regarding preventive measures for TORCH disease includes the following parts: The knowledge base regarding toxoplasmosis consists of (22) items, chickenpox consists of (28) items, hepatitis B consists of (19) items, rubella consists of (20) items, cytomegalovirus consists of (31) items, and knowledge regarding herpes simplex virus consists of (24) items. The researcher distributed the instrument to (17) experts with more than ten years of experience in the specialty to ensure the instrument's validity and to confirm the accuracy, relevancy, and adequacy of the questionnaires before they were ready for sample collection. ...
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TORCH infections cause congenital anomalies throughout the gestation period that can cross the placenta and damage the fetus. The study aimed to assess the nurse midwife’s knowledge regarding preventive measures for TORCH infections. A descriptive design study was conducted on 138 nurse-midwives in maternity teaching hospitals in Babylon province using self-administered questionnaires. The data were analyzed by using descriptive statistics (frequency and percentage). A chi-square test was used to analyze categorical variables. The P-value was determined using a P-value of 0.05 to determine statistical significance. Results: The mean age and standard deviation (SD) for nurse-midwives in the study was 34.11+8.967; the majority of the sample was (37.7%) reported at age 21–30 years. The majority of the study participants (69.6%) had no prior knowledge of TORCH diseases. The level of knowledge about TORCH disease prevention is low.93% of nurse-midwives had moderate knowledge. There was a significant relationship between nurse-midwives’ knowledge of TORCH diseases and their education level, their years of experience, and training sessions at a p-value of 0.05.
... Molluscum contagiosum, a related poxvirus, also causes cutaneous lesions and can be transmitted via both skin-to-skin contact and sex [23]. Herpes simplex virus type 2-while predominantly transmitted sexually-can also be transmitted via close skin-to-skin contact [24]. Similarly, Treponema pallidum, the cause of syphilis, is predominantly transmitted through sex [25]. ...
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The global outbreak of Mpox virus constitutes an international public health emergency. Reports have highlighted 1) a temporal association between sexual activity and Mpox disease, 2) an association between specific sexual practices and location of lesion development, 3) a high frequency of sexual practices conferring risk for other sexually transmitted infections among cases of Mpox, 4) that Mpox virus can be isolated from sexual fluids, 4) that isolated virus is infectious, and 5) a high frequency of anogenital lesions prior to disease dissemination suggesting direct inoculation during sexual activities. Finally, a growing body of evidence suggests that sexual transmission is the predominant mode of transmission for Mpox virus. We therefore conclude that Mpox is a sexually transmitted disease. Labeling it as such will help focus public health interventions, such as vaccinations, testing, and treatment, as well as facilitate focused awareness and education programs towards behavioral modifications to reduce exposures.
... The experiment was performed on a 24-well plate and then inoculated with HSV-1 (200 PFU). The compounds were administered 1 hour before and after infection (1,2,4,6,12,18, and 24 hours later). After 48 hours of infection, 3 × EC 50 was loaded into the wells at a specified time. ...
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Background: Herpes simplex virus type 1 (HSV-1) causes serious illness in humans, especially in newborns and immunocompromised hosts. Public health requires the development of new, less toxic anti-HSV-1 drugs. Objectives: This study aimed to evaluate the potential anti-herpesvirus activity of natural products in an extensive library of 133 compounds by examining viral titers and the number of viral plaques. Methods: (S)-10-hydroxycamptothecin (10-HCPT) as an inhibitor against viral DNA replication in the lowest concentration ranges from a set of natural products consisting of screening 133 compounds. Each step of the viral replication cycle of HSV-1 on A549 cells was evaluated with different assays, including adsorption, penetration, time-of-addition assay, and quantitative polymerase chain reaction (PCR). The respective antiviral effects on HSV-1AN95 infection were assessed in vitro. Results: 10-HCPT was found to be a potent inhibitor of HSV-1 infection in the lowest concentration range from screening of a natural product library. The results showed that 10-HCPT significantly affects HSV-1 viral plaque formation inhibition, with a half maximal effective concentration (EC50) of 0.07 μM. The time of addition assay suggested that 10-HCPT had a viral inhibitory effect when added 8 hours after infection. It was further confirmed by reducing the expression of late viral genes including glycoprotein (g) and viral protein (VP) (gB, gD, gH, VP1/2, and VP16) 4 hours after infection in the 10-HCPT treatment group compared to positive controls by quantitative real-time PCR. The Western blotting results are inconsistent with other reported results. It showed that 10-HCPT did not affect gD and ICP4 during HSV-1 infection, and 10-HCPT appeared to affect other genes in the immediate-early (IE) and late (L) steps. Conclusions: 10-HCPT demonstrated anti-HSV activity on HSV-1. Their dose-dependent antiviral activity showed that specific cellular components might mediate their function rather than cytotoxicity. This survey suggests a new outlook in exploring effective treatment options for HSV-1 infections.
... 27 Human herpes simplex viruses similarly can be transmitted via close contact and through contact with bodily fluids during sex. 8 Similarly, Treponema pallidum pallidum, the cause of syphilis, is predominantly transmitted through sexual contact, 28 yet historical reports before the routine use of protective gloves frequently noted syphilitic lesions on the fingers of physicians acquired via nonsexual skin-to-skin contact, 29,30 and via human bites. 31 Thus, universality of sexual transmission is not a requisite of sexually transmitted infections. ...
... Nonetheless, continual clinical usage of the aforementioned compounds can develop into drug-resistant. 7,8 The rate of ACV resistance is usually low among the immunocompetent patients; however, the rate of resistance has significantly increased to 14% from 5% in bone marrow transplant recipients. 9,10 The rise of ACV-resistant strains demands prolonged and challenging treatment, with expected relapses and treatment failure. ...
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Background: Herpes simplex virus-type 1 (HSV-1) can cause diseases, especially amongst neonates and immunocompromised hosts. Hence, developing a novel anti-HSV-1 drug with low-level toxicity is vital. Triptolide (TP), a diterpenoid triepoxide is a natural product with range of bioactivity qualities. Methods: In this study, viral infection was assessed in different phases of the HSV-1 replication cycle on A549 cells, using various assays, such as adsorption inhibition assay, penetration inhibition assay, time-of-addition assay, and quantitative polymerase chain reaction (qPCR). Results: The results indicate that TP can effectively inhibit HSV-1 infection in the lowest range of concentration. TP exhibited significant inhibitory effect on HSV-1 plaque formation, with 50% effective concentration (EC50) of 0.05 µM. Furthermore, the time-of-addition assay suggests that TP has viral inhibitory effects when it was added less than 8 h postinfection (h.p.i.). This result is further confirmed by decline in the expression viral immediate-early genes (ICP4, ICP22, and ICP27) in 6 h.p.i in the TP-treated group compared to the control group, evaluated by real-time qPCR. The Western blotting result was also consistent with the previous findings, which confirms that TP can positively affect ICP4 during HSV-1 infection. Conclusions: The TP also showed antiviral activity against HSV-1. This dose-dependent activity is an indication of a particular cellular component, rather than cytotoxicity that has mediated its function. Finally, the result suggest a new approach for an effective treatment option of the HSV-1 infections.
... Moreover, other viral pathogens such as human papilloma virus or herpes simplex virus have a huge prevalence in the population. More than 290 million women are infected by human papillomavirus (HPV), one of the most common STI, and more than 530 million people are infected with the herpes simplex virus-2 (HSV-2) [3,4]. Focusing on HIV-1 or HSV-2 viral infections, current treatments are only focused on mitigating or modulating pain and treating clinical symptoms, but not on preventing infections or on curing them. ...
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Background The absence of an effective treatment and vaccine in HIV-1 pandemic place preventive strategies such as safety and effective microbicide development as a central therapeutic approach to control HIV-1 pandemic nowadays. Results Studies of cytotoxicity, immune population status, inflammation or tissue damage and mainly prophylactic inhibition of HIV-1 infection in vaginal human explants demonstrate the biosafety and effectivity of G2-S16 dendrimer. Human explants treated with G2-S16 dendrimer or treated and HIV-1 infected do not presented signs of irritation, inflammation, immune activation or T cell populations deregulation. Conclusions Herein we conclude that G2-S16 dendrimer has demonstrated sufficient efficacy, biosafety, effectivity and behavior in the closest to the real-life condition model represented by the human healthy donor vaginal tissue explants, to raise G2-S16 dendrimer as a promising candidate to clinical trials to develop an effective microbicide against HIV-1 infection. Graphical Abstract
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Collectively, these results showed that HSV-2 is taken up by human vaginal epithelial cells through an endosomal-lysosomal pathway in association with LAMP3, which plays a crucial role in the enhancement of HSV-2 replication. These findings provide the basis for the future design of antiviral agents for prophylactic measures against HSV-2 infection.
Monkeypox, a milder disease compared to smallpox, is caused by a virus initially discovered and described in 1958 by the prominent Danish virologist von Magnus, who was investigating an infectious outbreak affecting monkey colonies. Currently, officially starting from May 2022, an outbreak of monkeypox is ongoing, with 51,000 cases being notified as of September 1, 2022 – 51,408 confirmed, 28 suspected, and 12 fatalities, for a grand total of 51,448 cases. More than 100 countries and territories are affected, from all the six World Health Organization (WHO) regions. There are some striking features, that make this outbreak rather unusual when compared with previous outbreaks, including a shift in average age and the most affected age group, affected sex/gender, risk factors, clinical course, presentation, and the transmission route. Initially predominantly zoonotic, with an animal‐to‐human transmission, throughout the last decades, human‐to‐human transmission has become more and more sustained and effective. In particular, clusters of monkeypox have been described among men having sex with men (MSM), some of which have been epidemiologically linked to international travel to non‐endemic countries and participation in mass gathering events/festivals, like the “Maspalomas (Gran Canaria) 2022 pride”. This review will specifically focus on the “emerging” transmission route of the monkeypox virus, that is to say, the sexual transmission route, which, although not confirmed yet, seems highly likely in the diffusion of the infectious agent. This article is protected by copyright. All rights reserved.
Background: Herpes simplex virus (HSV) is a widely distributed human pathogen that is known for its ulcerative lesions at the infection site. HSV can cause persistent infection in the host that is often followed by a period of latency within the neurons. Considering the high rate of HIV infection in South Africa, it is important to assess the seroprevalence of HSV with a focus to determine the epidemiological association between HSV-DNA and HIV-1 in the population. Methods: A total of 44 sera samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of the 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The PCR results, with the use of type specific primers, showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using the chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: There is a significant positive association between HSV-2 and HIV-1 in the study population. Our study shows that some of the HSV-2 isolates are not related to the clinical isolate SD90e from South Africa, suggesting diversity in HSV-2 viral transmission.
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Autophagy is a conserved catabolic process of the cell, which plays an important role in regulating plethora of infections. The role of autophagy in Herpes simplex virus-2 (HSV-2) infection is unknown. Here, we found that HSV-2 does not allow induction of an autophagic response to infection, but maintains basal autophagy levels mostly unchanged during productive infection. Thus, we investigated the importance of basal autophagy for HSV-2 infection, using pharmacological autophagy suppression or cells genetically deficient in an autophagy-essential gene (ATG5). Interference with basal autophagy flux in cells significantly reduced viral replication and diminished the infection. These results indicate that basal autophagy plays an indispensable role required for a productive infection. Importantly, this study draws a sharp distinction between induced and basal autophagy, where the former acts as a viral clearance mechanism abrogating infection, while the latter supports infection.
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Unlabelled: We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4(+) and CD8(+) T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model. Importance: HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.
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Herpes simplex virus 1 fuses with the plasma membrane of a host cell, and the incoming capsids are efficiently and rapidly transported across the cytosol to the nuclear pore complexes, where the viral DNA genomes are released into the nucleoplasm. Using biochemical assays, immunofluorescence, and immunoelectron microscopy in the presence and absence of microtubule depolymerizing agents, it was shown that the cytosolic capsid transport in Vero cells was mediated by microtubules. Antibody labeling revealed the attachment of dynein, a minus end–directed, microtubule-dependent motor, to the viral capsids. We propose that the incoming capsids bind to microtubules and use dynein to propel them from the cell periphery to the nucleus.
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Herpesviruses exemplified by herpes simplex virus-1 (HSV-1) attach to cell surface heparan sulfate (HS) for entry into host cells. However, during a productive infection, the HS moieties on parent cells can trap newly exiting viral progenies and inhibit their release. Here we demonstrate that a HS-degrading enzyme of the host, heparanase (HPSE), is upregulated through NF-kB and translocated to the cell surface upon HSV-1 infection for the removal of HS to facilitate viral release. We also find a significant increase in HPSE release in vivo during infection of murine corneas and that knockdown of HPSE in vivo inhibits virus shedding. Overall, we propose that HPSE acts as a molecular switch for turning a virus-permissive ‘attachment mode’ of host cells to a virus-deterring ‘detachment mode’. Since many human viruses use HS as an attachment receptor, the HPSE-HS interplay may delineate a common mechanism for virus release.
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Herpes simplex virus-1 (HSV-1), like all herpesviruses, is a large complex DNA virus containing up to 16 different viral membrane proteins in its envelope. The assembly of HSV-1 particles occurs by budding/wrapping at intracellular membranes producing infectious virions contained within the lumen of cytoplasmic membrane-bound compartments that are then released by secretion. To ensure incorporation of all viral membrane proteins into the envelope, they need to be localized to the appropriate intracellular membranes either via the endocytic pathway or by direct targeting to assembly sites from the biosynthetic secretory pathway. Many HSV-1 envelope proteins encode targeting motifs that direct their endocytosis and targeting, while others do not, including the essential entry proteins gD and the gH/gL complex, and so it has been unclear how these envelope proteins reach the appropriate assembly compartments. We now show that efficient endocytosis of gD and gH/gL and their incorporation into mature virions relies upon the presence of the HSV-1 envelope proteins gM and the gK/pUL20 complex. Our data demonstrate both redundant and synergistic roles for gM and gK/pUL20 in controlling the targeting of gD and gH/L to the appropriate intracellular virus assembly compartments.
These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR-12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment-related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs.
Globally, herpes simplex virus type 2 (HSV-2) infection is the most common cause of genital ulcer disease. Effective prevention strategies for HSV-2 infection are needed to achieve the goals of the World Health Organization global strategy for the prevention and control of sexually transmitted infections. We assessed the effectiveness of pericoital tenofovir gel, an antiviral microbicide, in preventing HSV-2 acquisition in a subgroup of 422 HSV-2-negative women enrolled in the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 study, a double-blind, randomized, placebo-controlled trial. Incident HSV-2 cases were identified by evidence of seroconversion on an HSV-2 IgG enzyme-linked immunosorbent assay between study enrollment and exit. A confirmatory analysis was performed by Western blot testing. The HSV-2 incidence rate was 10.2 cases per 100 person-years (95% confidence interval [CI], 6.8 to 14.7) among 202 women assigned to tenofovir gel, as compared with 21.0 cases per 100 person-years (95% CI, 16.0 to 27.2) among 222 women assigned to placebo gel (incidence rate ratio, 0.49; 95% CI, 0.30 to 0.77; P=0.003). The HSV-2 incidence rate among the 25 women with vaginal tenofovir concentrations of 10,000 ng per milliliter or more was 5.7 cases per 100 person-years, as compared with 15.5 cases per 100 person-years among the 103 women with no detectable vaginal tenofovir (incidence rate ratio, 0.37; 95% CI, 0.04 to 1.51; P=0.14). As confirmed by Western blot testing, there were 16 HSV-2 seroconversions among women assigned to tenofovir gel as compared with 36 among those assigned to the placebo gel (incidence rate ratio, 0.45; 95% CI, 0.23 to 0.82; P=0.005). In this study in South Africa, pericoital application of tenofovir gel reduced HSV-2 acquisition in women. (Funded by the U.S. Agency for International Development and others; number, NCT00441298.).
Significance Entry of enveloped viruses into the cell requires the activation of viral glycoproteins, often mediated by cellular receptors. Herpesviruses infect cells via a multipartite system, which includes species-specific glycoproteins plus conserved apparatus gH/gL and gB. HSV makes use of αvβ6- or αvβ8-integrins as gH/gL receptors. The interaction of HSV gH/gL with integrins resulted in the dissociation of gL. The dissociation took place if all the actors of the entry apparatus were present, i.e., under conditions that lead to glycoprotein activation and virus entry. We propose that ( i ) gL is a regulator of gH and prevents its activation until integrins promote gL dissociation from gH/gL. ( ii ) Dissociation from an inhibitory regulator represents a previously unidentified mechanism of activation of viral fusion glycoproteins.
The clinical course and complications of 268 patients with first episodes and 362 with recurrent episodes of genital herpes infection were reviewed. Symptoms of genital herpes were more severe in women than in men. Primary first-episode genital herpes was accompanied by systemic symptoms (67%), local pain and itching (98%), dysuria (63%), and tender adenopathy (80%). Patients presented with several bilaterally distributed postularulcerative lesions that lasted a mean of 19.0 days. Herpes simplex virus was isolated from the urethra, cervix, and pharynx of 82%, 88%, and 13% of women with first-episode primary genital herpes, and the urethra and pharynx of 28% and 7% of men. Complications included aseptic meningitis (8%), sacral autonomic nervous system dysfunction (2%), development of extragenital lesions (20%), and secondary yeast infections (11%). Recurrent episodes were characterized by small vesicular or ulcerative unilaterally distributed lesions that lasted a mean of 10.1 days. Systemic symptoms were uncommon and 25% of recurrent episodes were asymptomatic. The major concerns of patients were the frequency of recurrences and fear of transmitting infection to partners or infants.