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Accurate Info for Patients
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Genital herpes: The basics more patients should know
DISCLAIMER: Rational Vaccines (RVx) is providing this “Accurate Info for Patients”
document as a resource to summarize (1) principles that define how HSV infections are controlled
and (2) present options for the diagnosis, management, and prevention of genital HSV infections.
Patients and doctors are individually responsible for how they choose to use this information.
UPDATES: The “Accurate Info” portion of RVx’s website and this document will be updated
quarterly based on feedback from doctors and patients.
OVERVIEW: The Chief Science Officer of RVx, William P. Halford, has been studying the
latency-replication balance of herpes simplex virus since 1991 (see Dr. Halford’s Biosketch). The
document that follows is the net result of interweaving the (1) theoretical underpinnings of HSV’s
in vivo biology (reviewed in Halford & Gebhardt, 2011) with (2) the perspective of genital herpes
sufferers who experience disease symptoms more than 30 days per year. This document
summarizes three areas of knowledge that may help herpes sufferers arrive at a better
understanding of how to manage their symptoms and risk of HSV transmission.
1. The Biology of Herpes Simplex Virus (HSV) Infections.
2. The Relationship between Latent HSV Infections and Genital Herpes Disease.
3. Strategies to Manage Genital Herpes: Present and Future.
OTHER RESOURCES:
 Beauman, 2007. Genital Herpes: A Review
 Warren, 2009. The Good News About the Bad News of Herpes: Everything You Need to Know
1. The Biology of Herpes Simplex Virus (HSV) Infections
1-A. Herpes Simplex Virus Serotype 1 vs 2 (HSV-1 vs HSV-2)
HSV-1 and HSV-2 are two nearly identical viruses that share ~75 co-linear genes. HSV-1 and
HSV-2 produce a similar spectrum of disease. The main difference between HSV-1 and HSV-2
is that they are two different serotypes of the same virus. Due to single amino-acid changes
sprinkled through HSV-2’s 75 proteins (relative to HSV-1 proteins), HSV-2 has evolved the ability
to superinfect people already infected with HSV-1. The use of multiple related serotypes to allow
essentially the same microbe to infect humans more than once (and thus evade pre-existing
immunity) is not unique to HSV; Streptococcus pneumoniae, rhinovirus (a cause of the common
cold), and human papilloma virus each have >100 serotypes that are all biologically the same
microbe, but which contain enough amino acid changes to side-step pre-existing immunity to other
serotypes of the same microbe.
In this document, the terms HSV-1 and HSV-2 will be used to denote specific viruses when
relevant. However, because the biology of HSV-1 and HSV-2 infections are similar in principle,
the term “HSV” will be used wherever possible to indicate that the principles under discussion are
probably relevant to both HSV-1 and HSV-2.
HSV-1 and HSV-2 both cause primary genital herpes. In some patient populations, HSV-1 is
a more common cause of genital herpes than HSV-2. It has widely been stated that HSV-2 is the
predominant cause of recurrent genital herpes, which most doctors take to mean that HSV-1 never,
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or only rarely, causes recurrent genital herpes. There is a dearth of evidence to support this
sweeping conclusion that was made in the 1970s before we had the scientific means to fully vet
the hypothesis. In the 21st century, HSV-1 appears to be the predominant cause of genital and
neonatal herpes (Bernstein, et al, 2013; Jones, et al, 2014). Thus, HSV-1 is equally capable of
productive replication in the genital tract and lower spinal ganglia as HSV-2, and likewise genital
HSV-1 infections may be transmitted to a sexual partner or to a child during childbirth.
The fact that many medical practitioners still believe HSV-2 is the only relevant cause of genital
herpes is representative of the larger problem that doctors are too often working with outdated
information. Being 80% right is still “wrong enough” to create serious problems with the decisionmaking process used to diagnose and manage genital herpes.
1-B. Primary HSV Infections. Viral replication is the process by which any human virus, including
HSV, (1) enters cells in the body and (2) initiates a process of replication (amplification) that
increases the number of viruses by 10- to 100-fold over the course of a few hours. The details of
HSV replication in a single cell are too complex to warrant discussion here. However, the logic
of the process is important. Like a computer virus, an actual virus is a piece of code, which in the
case of HSV is a small piece of linear, double-stranded DNA that is about 150,000 base pairs long.
For non-scientists, you can think of this as a book that is 75 pages long, where most pages have
between 1,000 and 4,000 characters per page. In the context of HSV, each ”page” is called a viral
gene and refers to one segment of the code. All of the characters in the “whole book” are called
the HSV genome. Against that background, HSV replication proceeds, as follows:
i. A small particle (virion) delivers the
HSV genome into a cell, which is
shown binding to the upper left corner
of a single cell in the adjacent Figure.
ii. The virion releases the whole HSV
genome into the cell and this is carried
to the nucleus (dark gray center).
There a subset of 5 immediate-early
(IE) genes make 5 IE proteins that start
a cascade of events that lead to HSV
replication, which is the equivalent of
photocopying a whole book (the HSV
genome) a few hundred times.
iii. As the HSV genome is “photocopied,” the increasing numbers of HSV genomes encode more
and more viral proteins (1 protein per viral gene), and the new viral proteins assemble around the
new HSV genomes to form new infectious virions (particles). These virions are shed from the
virus-infected cell and may spread within that person or may be transmitted to another person. To
summarize, one infectious HSV virion enters one human cell and within 12 – 18 hours that cell
may release up to 100 new infectious HSV virions that may either (1) spread to neighboring cells,
propagating the infection, or may (2) be transmitted to another persion.
iv. Returning to the scale of a person, this process allows (1) HSV to initially infect the skin of the
penis (or labia, vaginal mucosa, or anus) and (2) within 24 hours hundreds of newly synthesized
infectious HSV virions are able to infect nerve fibers in the skin and move back into the peripheral
nervous system and throughout the infected person’s body. The site of the life-long HSV infection
is not in the skin where the infection starts, but rather is in the ganglia (collections of nerve cell
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bodies) that emanate off the left and right side of the lower
spine (top of red arrow in adjacent Figure). Transport of HSV
genomes up nerve fibers from the skin to the ganglia is
mediated by a process called retrograde axonal transport,
which is akin to an HSV virion hopping on an escalator that
carries it from the skin to the spine (depicted as red arrow in
the adjacent Figure). Once HSV infection reaches the spine,
a life-long infection is established in the sacral ganglia.
Because of the rapidity of viral replication, initially
microscopic HSV infections go from being undetectable to
the human eye (i.e., asymptomatic) to detectable about 5 days
after a transmision event. In 80% of cases of HSV infection,
the innate immune system suppresses the infection and the
person remains asymptomatic and unaware of the infection for
the duration of their life. However, ~2% of HSV-infected persons will progress to a lifetime of
genital herpes that recurs more than 4 times per year. Although “only 10% of HSV infections”
cause overt herpes symptoms, 4 billion people are infected; >100 million people suffer with
recurrent herpetic disease caused by HSV-1 or HSV-2.
1-C. Latent HSV Infections. Dr. Halford obtained his PhD for
studies of persistent immune responses in HSV latently infected
ganglia (Halford, et al, 1996), and invested more than a decade
studying how ICP0 regulates HSV’s latency-replication balance
(NIH grants that supported this work). A synopsis of the biology
of latent HSV infections is presented, as follows:
i. HSV latency is not as silent as most doctors have been led to
believe. Simply because a patient does not exhibit external
symptoms of active HSV disease, does not mean that subclinical
HSV reactivation events are not in progress. To the contrary, 20
years of literature suggests subclinical HSV reactivations are a
frequent (weekly) event where a single latently infected neuron
(out of a pool of thousands) re-initiates productive HSV
replication. Hence, 2% of the human population is shedding
infectious HSV virions that may be transmitted to others on any
given day. Most people shedding infectious HSV virions do not
exhibit herpes symptoms at the time.
ii. HSV latency may, in essence, be described as an equilibrium
between the virus and host. The host immune system cannot
destroy HSV-infected neurons because the virus downregulates
(turns OFF) viral protein synthesis when CD8+ T cells approach tracts of HSV infected neurons.
These T cells encircle (wall off) HSV-infected neurons and non-cytolytically suppress viral
replication through the secretion of cytokines such as interferon- (reviewed in Halford &
Gebhardt, 2011; illustrated above).
iii. In persons who have HSV DNA in their spinal ganglia, the latent infection is stable and consists
of a population of hundreds to thousands of HSV latently infected neurons. Each latently infected
neuron may harbor >300 latent HSV genomes in the form of circular DNA molecules that have
the potential to re-awaken (reactivate) when the correct stimuli are provided. A latent HSV
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infection cannot be “cured” by removing all of the thousands of copies of latent HSV DNA from
the body, and patients should not be duped into believing this is a practical reality. Claims that
latent HSV infections may be “cured” with homing endonucleases that destroy 100% of latent
HSV genomes are not credible because they are inconsistent with the evidence. Such DNA cutting
reactions typically occur with <10% efficiency under the best of conditions. Moreover, this low
efficiency of HSV DNA cutting should only decrease in an intact animal or human patient.
1-D. Regulation of HSV’s Latency-Replication Balance. Scientists lack a detailed, mechanistic
understanding of how HSV’s latency-replication balance is controlled. However, a general
description of the relevant factors provides a framework for understanding the process.
i. The HSV genome is arranged in discrete blocks of code known as regions, as illustrated in
the Figure below. The unique-long (UL) and unique-short (US) regions are, in essence, a
bag of 68 viral genes that predominantly encode machinery required for HSV replication.
ii. The regions of the HSV genome that regulate HSV’s latency-replication balance (i.e., the
ON-OFF switch) reside in two 15-kilobase repeated regions, RL and RS, that control the
expression of 3 of the 4 viral IE regulatory proteins; namely, ICP4, ICP0, and ICP22.
iii. The short-repeated (RS) regions encode ICP4, a viral IE protein that serves as HSV’s major
transcriptional regulator, which is
essential to either positively or
negatively regulate HSV gene
expression (i.e., the foundational
hardware of the ON-OFF switch).
iv. The long-repeated (RL) regions
control HSV’s latency-replication
balance. Two genes that influence
the process are the latencyassociated transcripts (LAT) and
infected cell protein 0 (ICP0). The adjacent L/ST and ICP34.5 genes play important roles
as well. In simple terms, the available evidence suggests that (1) the L/ST-ICP34.5 genes
may control the timing of HSV’s exit from productive replication in neurons; whereas (2)
the LAT-ICP0 genes may control the maintenance and reactivation of latent HSV genomes.
v. The ICP0 and ICP34.5 genes encode proteins that are essential for HSV to resist repression
by the host antiviral response (i.e, the human interferon response). Hence, a simple view
of HSV’s latency-replication balance, which is consistent with the available evidence, is
that HSV’s capacity to alternate between being (1) interferon-resistant (ICP0 and ICP34.5
are expressed) and (2) interferon-sensitive (ICP0 or ICP34.5 fail to accumulate) may lie at
the heart of how the HSV genome “chooses” between productive replication or latent
infection in neurons in vivo (reviewed in Halford & Gebhardt, 2011).
vi. During "latency,” HSV gene expression appears to be restricted to the regulatory regions
in the RL and RS regions, such that a collection of regulatory gene products may maintain
the latent state. Viral replication cannot proceed because the 68 HSV genes in the UL and
US regions are silent. The HSV genome’s UL region appears to be insulated from
transcriptional activity in the regulatory RL regions by blocks of GC-rich direct repeats.
Such DNA-based “terminators” and virus-encoded “anti-terminators” that regulate RNA
polymerase’s processivity (i.e., ability to “bulldoze” through terminators) lies at the heart
of how  phage regulates its equivalent of a latency-replication balance in E. coli.
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1-E. Reactivation of Latent HSV Infections
 At the center of HSV’s latency-replication balance lies the ICP0 gene, which encodes the
master regulator of this balance. ICP0 was first identified as a protein that transformed HSV’s
major transcriptional regulator, ICP4, from a weak to a highly potent activator of viral mRNA
synthesis. Accumulation of ICP0 causes the HSV genome to abruptly tip towards productive
replication, whereas absence of ICP0 strongly favors establishment of a silent HSV infection.
 Anything that triggers ICP0 synthesis will promote reactivation of a latent HSV infection.
Many of the stressors known to trigger HSV reactivation in animal models (ultraviolet light,
hyperthermic stress, irritation of the site of primary HSV infection) have been shown to
activate a rapid increase in ICP0 mRNA synthesis, which would tip HSV’s latency-replication
balance towards reactivation. In the context of genital herpes, reactivation of latent HSV
genomes residing in the sacral ganglia would create a new, active area of HSV replication in
the lower spine (which might produce a backache). If this initial single-cell reactivation event
were not suppressed by the immune system within the first 24 hours, new infectious HSV
virions would be produced (as described in Section 1B) and would be returned to the
epithelium via anterograde axonal transport (i.e., blue arrow in adjacent Figure). Within 3 to
4 days, if HSV replication were not suppressed in the skin, the n the ongoing spread of the
reactivated HSV infection would manifest as an area of redness that would eventually progress
to a lesion at the site innervated by the HSV latently infected nerve fiber that reactivated (e.g.,
the epithelium of the penis, labia, vaginal mucosa, or anus). Typically, 7 to 10 days of active
viral spread would be required from the initial HSV reactivation event in a single neuron of
the lower spine to progress to lesions the size of those pictured in the adjacent Figure.
 A critical concept that many doctors and patients miss is that HSV reactivation is not the same
as recurrent herpetic disease. HSV reactivation
occurs in a single HSV latently infected neuron and
leads to the release of new infectious virions (per the
scheme shown in Section 1B). Considering that a
person may contain hundreds or thousands of HSV
latently infected neurons distributed through ganglia
of their lower spine, single-cell HSV reactivation
events are likely occurring at least once per week in
all HSV latently infected persons; even those who are
asymptomatic. Most individuals mount an immune
response that controls HSV reactivation events in the
first 48 – 72 hours, and thus these individuals do not
experience the later symptoms of herpetic disease.
Those individuals who require 10 to 14 days to
suppress a HSV reactivation event will (1) shed
infectious virus from 3 to 5 days post-reactivation in
the absence of symptoms and (2) will manifest areas of redness or open lesions after 6 days
post-reactivation. In summary, HSV reactivation is a molecular event that occurs in a single
cell, whereas recurrent herpes symptoms only become apparent 5 or more days later. The
available evidence suggests that fewer than 5% of single-cell HSV reactivation events progress
to what a well-trained doctor would recognize as the symptoms of recurrent herpes.
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2. The Relationship between Latent HSV Infections and Genital Herpes Symptoms
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Over 3 billion people are infected with HSV-1, and HSV-1 is the predominant cause of
genital herpes in younger age groups. Although many doctors are taught that HSV-2 is the
primary cause of recurrent genital herpes, the evidence to support this supposition is limited
at best. The literature of the past decade indicates that, in the 21st century, HSV-1 and
HSV-2 are both significant causes of genital herpes.
The most obvious functional difference between HSV-1 and HSV-2 is that (1) HSV-2 kills
host cells more quickly (i.e., is more cytopathic) and (2) HSV-2 infection spreads cell-tocell more rapidly than HSV-1. It would appear HSV-2 has evolved these more aggressive
traits to allow it to efficiently superinfect persons already infected with HSV-1.
The severity of primary HSV infection can be hugely influenced by two variables:
- trauma to epithelium at time of HSV transmission (Fig. 1 of Halford, et al., 2004)
- immune status at the time of primary HSV infection (Fig. 6 of Halford, et al., 2005)
Examples of the first principle include women who have had a “Brazilian” pubic hair
removal just prior to contracting HSV and men who shave over primary herpes lesions. In
both cases, a compromised epithelial barrier promotes more severe herpetic disease.
As the duration of primary HSV infection increases, the risk of recurrent herpetic disease
increases. Primary genital herpes may last as long as 2 months with frequent recurrences
spanning the first year. In contrast, 80% of primary HSV infections are so brief that no
symptoms are noted. The duration of the primary infection will be proportional to (1) the
number of HSV latently infected neurons colonized in the lower spine and (2) the copy
number of latent HSV genomes an individual carries for the remainder of their life. This
“viral DNA load” may vary widely from person-to-person, and may range from less than
1,000 to >1,000,000 copies of the latent HSV genome. As the reservoir of HSV latently
infected neurons increases, so do the odds of recurrent herpetic disease.
Among the greatest challenges for clinicians in diagnosing herpetic disease is that HSV
infections may produce a wide variety of symptoms. Medical textbooks tend to emphasize
“typical” herpes symptoms, but less than 20% of HSV-infected persons will present with
these symptoms. Likewise, only a subset of patients with recurrent genital herpes will have
the “typical” 4 outbreaks per year. Patients who are latently infected with HSV may suffer
from recurrent herpes symptoms that impacts them anywhere from 0 - 100% of the days in
any calendar year. Rules are only useful when they are applicable most of the time. With
recurrent genital herpes, it is simply not useful to think in terms of a “median case of
herpes,” because 80% of HSV infections are completely asymptomatic and 1-2% are far
more chronic and debilitating than the “typical” presentation.
Clinicians should think of recurrent genital herpes as being highly variable in (1) frequency
of outbreaks, (2) duration of outbreaks, and (3) spatial extent of skin symptoms (localized
or widespread across more than one dermatome). Additionally, patients may exhibit
symptoms that are more internal than external in nature, such as chronic herpes-induced
neuralgia. The clinical presentation of herpes zoster provides some context for considering
what is possible. HSV-1 and HSV-2 tend to cause more localized symptoms at any one
point in time, but patients’ symptoms may alternate between the genitalia, buttocks, thighs,
and/or anus (areas innervated by the sacral ganglia). The review of Beauman, 2007
considers some “atypical” presentations of genital herpes.
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Patients who experience the most protracted primary HSV-1 or HSV-2 infections are at the
greatest risk for having high-level complications associated with recurrent genital herpes,
including (1) chronic neuropathic pain and/or (2) multiple sites of HSV recurrences that
rotate from the left and right sides of the body. The latter symptoms indicate that latent
HSV infections were established in multiple spinal ganglia.
 Many so-called “atypical” herpes symptoms make a great deal of sense if one understands
the theoretical underpinnings of the biology of HSV infections.
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3. Strategies to Manage Genital Herpes: Present and Future
The biology of latent HSV infections is presented above in terms
of an equilibrium model, which effectively reduces to three points:
1. When viral activators accumulate in HSV-infected neurons,
the virus overcomes interferon (host)-induced repression
and active replication occurs.
2. When viral activators fail to accumulate, HSV replication in
neurons is suppressed by the host immune response.
3. Most HSV reactivation events do not appear to kill their host
neurons. Hence, the reservoir of latently infected neurons
does not shrink over time, and most sufferers experience
their outbreaks at the same site over and over again because
the same neurons repeatedly support reactivation events.
Below, the factors that influence recurrent genital herpes are
described in the same terms. In essence, HSV reactivation is like an
idling car that is temporarily stopped. There are two options to get
it moving. You can (1) punch the gas to overpower the brakes (i.e.,
make more viral activators) or (2) release the brakes so the car starts
rolling (i.e., compromise immune control of HSV). Triggers of
HSV reactivation either i. increase production of viral activators; ii.
interfere with host immune control of HSV; or iii. both.
3-A. Avoidance of HSV Triggers. Triggers include activities that increase levels of stress-related
hormones, such as cortisol, or sunburn, local irritation of sites where herpes outbreaks occur, or
damage to the HSV latently infected nerve fibers (e.g., a back injury). In animal models, such
triggers tend to drive increased production of the viral IE activator protein ICP0, which promotes
reactivation. Alternatively, triggers may dampen the host immune response that controls a latent
HSV infection. Examples include alcohol consumption, anemia, systemic fever, or the
progesterone spike that precedes menstruation. Additionally, many foods trigger herpes outbreaks
in sufferers such as peanuts, chocolate, and coffee which have the potential to (1) drive expression
of viral activators (particularly stimulants like coffee) and/or (2) trigger food allergies that would
alter immune function. Knowing and avoiding activities that trigger herpes outbreaks is a simple
strategy used by many herpes sufferers to reduce the frequency of their symptoms.
3-B. Pros and Cons of Acyclovir-Like Drugs. Acyclovir was developed in the 1970s, and
functions as a chain terminator of viral DNA synthesis in HSV-infected cells. Although it is
efficient at blocking HSV replication in a laboratory setting, acyclovir’s efficacy in patients is
limited by its poor solubility, and oral acyclovir is additionally limited by poor absorption from
the gut. Valacyclovir and famciclovir are related drugs that have the same mechanism of action,
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but which are slightly more soluble. In patients with recurrent genital herpes, acyclovir-like drugs
may be taken episodically as needed to shorten the duration of herpes outbreaks. However, for
this to be effective, the drugs must be taken at the earliest sign of the prodromal symptoms (nerve
tingling or pain) that precedes an outbreak. Alternatively, some patients are placed on daily
suppressive therapy to control their herpes outbreaks with acyclovir-related drugs. For some
patients, daily antiviral drugs are effective, but for many this is not the case. In two studies in
1988, it was shown that patients who took daily acyclovir prophylactically exhibited a decrease in
HSV-specific antibody levels. For others, acyclovir-related drugs may decrease the duration of
skin symptoms, but are ineffectual in preventing the pain and tingling sensations (neuralgia) that
accompany recurrent genital herpes. HSV-infected persons should absolutely consider acyclovirrelated drugs to manage their disease. However, patients should be realistic that acyclovir-related
drugs are not effective for controlling 100% of herpes symptoms in 100% of patients.
3-C. Pritelivir: A Better Antiviral Drug? In 2016, the first new class of anti-herpesviral drugs
appears to be close to reaching U.S. markets. This drug, pritelivir, functions as a helicase-primase
inhibitor of HSV replication. The chemical structure and mechanism of action of pritelivir are
completely unrelated to acyclovir-related drugs. Therefore, it is possible that combinations of
pritelivir and acyclovir-related drugs may be more effective than either drug alone. Initial clinical
trial results suggest pritelivir would be vastly superior to acyclovir-based antiviral drugs in terms
of its capacity to reduce herpes symptoms and the frequency of shedding of infectious HSV-2
virions (Wald, et al, 2014). However, it remains unclear when pritelivir will be available to the
public. Side-by-side comparative studies will be needed to determine if, in fact, pritelivir is more
effective for managing genital herpes than acyclovir-based drugs.
3-D. Why Better Herpes Treatment Options Are Needed. The current strategies medical
professionals rely upon to diagnose, manage, and prevent herpetic disease are in many ways
outdated. Recent advances in the understanding of the in vivo biology of HSV infections may be
exploited to yield better solutions, as opposed to relying upon acyclovir-based antiviral drugs.
Antiviral drugs may be improved upon, but the past 20 years of experience with acyclovirrelated drugs suggest that antiviral drugs alone are insufficient to stop the epidemic spread of HSV
infections from 4 billion carriers to >1 million uninfected persons every week. If antiviral drugs
were effective at preventing the spread of HSV infections, this should have been obvious by 2005.
However, to date, antiviral drugs have not curbed the rate of HSV-1 or HSV-2 transmission from
HSV latently infected carriers to naïve individuals.
At RVx, we believe better herpes solutions are possible today, and recommend the following
changes, which might improve the management and prevention of genital herpes:
1. Accurate Diagnosis and Prophylactic Vaccines for Discordant Couples. The host
immune response always serves as “the brakes” that restricts the spread of HSV. If genital
herpes patients are accurately diagnosed with HSV-1 versus HSV-2 genital herpes, then
patients with HSV-1 genital herpes may reduce the risk of sexual transmission by entering
into a relationship with the >50% of the population who already carry HSV-1.
Alternatively, an effective prophylactic HSV-1 or HSV-2 vaccine offered to a seronegative
partner would greatly reduce the risk of transmission of herpetic disease.
2. Proper management of genital herpes. Many doctors have been misled to believe that
management of genital herpes should focus exclusively on HSV (the virus). This approach
does not adequately consider the in vivo biology of HSV infections, which indicates that
latent HSV infections exist in an equilibrium that is controlled both by a gas pedal (the
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virus) and a braking system (the host immune response). If an antiviral drug is effective,
this will interfere with the virus replication (amplification) required for a HSV reactivation
event to progress to a recurrent herpes lesion. While this is sometimes helpful, ongoing,
subclinical HSV reactivation events may be required to keep the adaptive immune system
(antibodies and T-cells) adequately engaged in the active control of HSV replication.
Hence, patients often observe that while antiviral drugs may initially help control their
symptoms for 3 to 6 months, HSV-antibody levels (and likely HSV-specific T-cells) are
not maintained when patients take antiviral drugs every day. If the host immune response
becomes ineffective (no brakes), herpes sufferers note that the antiviral drugs “lose their
potency” and their recurrent herpes symptoms return. Learn more about how daily antiviral
drug suppression often erodes HSV antibody levels in patients.
3. Therapeutic HSV-2 vaccines: an underexplored treatment modality. The immune
system explains why (1) 80% of HSV infections are asymptomatic; (2) HSV infections are
devastating in newborns whose immune systems are under-developed; and why (3) HSV
infections progress to fatal outcomes in interferon-deficient individuals. The possibility
that the adaptive immune system may be “misfunctioning” (tolerized) in recurrent herpes
sufferers has not been carefully investigated. Clonal exhaustion of T cells is known to
occur when foreign antigens, like HSV proteins, are chronically present (Wherry and
Kurachi, 2015). The underlying cause of recurrent genital herpes in many sufferers may
reduce to “tolerization” of the adaptive immune system to HSV’s foreign proteins, which
would severely compromise immune control of latent HSV infections.
Therapeutic HSV-2 vaccines, such as the Agenus HerpV or Genocea GEN-003
vaccines, are being considered as a new treatment modality to break this potential stalemate
of “tolerance to HSV-2 immunogens.” However, like many failed HSV-2 subunit
vaccines, the GEN-003 and HerpV therapeutic HSV-2 vaccines only expose recipients to
2% of HSV-2’s potential immunogens. At RVx, we believe that the TheravaxHSV-2 vaccine
is far more likely to yield an effective therapeutic HSV-2 vaccine because it encodes up to
99.3% of HSV-2’s potential antigens. Clinical trials to test this concept are imminent.
3-E. Why genital herpes is most likely a vaccine-preventable disease. In recent years, biomedical
researchers have attempted to develop “subunit vaccines” to prevent genital herpes, AIDS, and
other infectious diseases. Subunit vaccines typically contain less than 2% of HSV-2’s antigens,
and are based on the premise that one small piece of HSV-2 may serve as an effective vaccine. To
date, all HSV-2 subunit vaccines tested in clinical trials have failed to prevent genital herpes.
RVx believes that our different approach, which uses rationally-engineered live vaccines that
retain 99% of HSV’s potential antigens, will be sufficient to end the herpes epidemic. Live viral
vaccines re-create every facet of a microbe’s life cycle, and fully prepare the human immune
system to do battle with the natural pathogen. Live viral vaccines have been used to prevent the
viral diseases of (1) smallpox, (2) yellow fever, (3) polio, (4) mumps, (5) measles, (6) rubella, and
(7) chickenpox. Never once, in the history of medicine, has a live-and-appropriately-attenuated
viral vaccine failed to stop the spread of its corresponding disease in the human population. RVx’s
ProfavaxHSV vaccines offer a similar opportunity to eradicate all forms of herpetic disease.
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