Biologisch
Medisch Centrum Epe| Waking a Herpes Virus
Arts Paul van Meerendonk Deze
site is opgericht door een zeer tevreden cliënt van het Biologisch Medisch
Centrum
Herpes is a huge health
problem. Twenty million to 30 million Americans have
recurrent genital herpes outbreaks, and 700,000 new
genital herpes simplex virus infections occur every
year. More than 2,000 babies are born with a herpes
infection annually, even though 40,000 caesarians
are performed due to a fear of transmitting herpes
from mother to child.
The herpes simplex virus is a
complex high-performance engine designed to
replicate itself. When it enters a human host, it
encounters an army of cellular defense proteins
designed to turn off these engines and prevent the
virus from multiplying.
But the herpes virus is
capable of fighting back. It can shut down attempts
by its host to block it. In skin abrasions and cells
lining the mouth or genitals of the host, the virus
prevails by overcoming the host’s cellular defenses.
Then, after the herpes virus
gets past its host’s cellular defenses and begins to
multiply, it infects the host’s neurons. Here a
different story takes place.
In neurons, the herpes virus
allows itself to be silenced by its host’s defenses
and lies dormant until it is activated by hormones
or stress on the neurons.
While the virus is dormant it
is not vulnerable to antiviral drugs, but when the
virus is fighting its host’s cellular defenses it is
vulnerable. That’s why Bernard Roizman, ScD, Joseph
Regenstein Distinguished Service Professor of
Virology and Chair of the Viral Oncology Laboratory
at the University of Chicago, and his colleagues are
focusing their herpes research on the mechanism by
which the host silences the virus. Their work is
supported by a two-year $581,604 grant from the
National Institutes of Health that has allowed them
to hire two fulltime employees, one at the
postdoctoral level and one technical assistant.
Waking a sleeping
giant
The primary health threat
posed by the herpes virus occurs when it is
reactivated from its dormant state and causes both
new lesions in the person who harbors the virus and
in others with whom the host comes into contact.
Today, individuals harboring
dormant viruses cannot be cured. One approach that
might cure herpes, however, is to disrupt the
silencing mechanism harbored in the host’s neurons.
This would allow the virus to multiply, at which
point the virus could be killed by newly designed
antiviral drugs.
To achieve this, Roizman and
his colleagues need to know the mechanism by which
the virus is silenced in neurons. “We know a lot
about host’s cellular defenses at the sites of entry
into the body,” he says. “Now, our foremost question
is whether the same defenses are operating in
neurons.”
If the answer is “yes,” the
researchers will be able to begin to develop drugs
that temporarily disrupt those defenses. “For now,
my University of Chicago research associates Haidong
Gu, MD, Grace Zhou and Te Du and I are designing
mutant test viruses that will act as ‘Trojan’
viruses aimed at elucidating the neurons’ defense
mechanism,” Roizman says.
A vaccine for herpes? Researchers discover
immune cells that suppress HSV-2 infection | Fox
News
A vaccine for herpes? Researchers
discover immune cells that suppress HSV-2 infection
Genital herpes is one of the most common types of
sexually transmitted infections (STI) in the United
States – as well as one of the most frustrating.
Characterized by periodic blisters on the genitals,
rectum or mouth, there is currently no cure for the
disease, and it can only be managed by antiviral
medications which help shorten outbreak periods.
However, a new study may provide hope for those
suffering from this STI. Researchers have identified
a subtype of immune cells that suppress outbreaks of
genital herpes caused by the herpes simplex virus
type 2 (HSV-2).
The discovery could lead to a vaccine capable of
preventing herpes lesions on people who have already
contracted the STI – or in other words, a vaccine
that could “clinically cure” an individual of herpes
symptoms.
The newly identified T-cells, called CD8αα+ T-cells,
reveal a great deal more information about genital
herpes than was initially known.
“What we found was that (these T-cells) are turned
on and making all sorts of antiviral substances,”
lead author Dr. Larry Corey, an internationally
renowned virologist and president and director of
the Fred Hutchinson Cancer Research Center in
Seattle, Wash., told FoxNews.com. “When the virus
reactivates, they are the first cells in to contain
the virus, and we showed they contain it very well.
They can contain it before the virus escapes above
the skin.”
Before this study, researchers believed that herpes
reactivation was controlled at the ganglion level of
the spinal canal area. But by using a technique
called laser capture, Corey and his colleagues were
able to biopsy and analyze the RNA in pieces of
human tissue from the dermal-epidermal junction (DEJ),
where the dermis – the outer layer of skin –
connects to the epidermis – the layer of tissue just
below the skin’s surface. The team discovered that
these CD8αα+ T-cells are located in the DEJ and are
responsible for controlling HSV-2 – implying that
herpes reactivation is controlled in the skin, not
the spine.
Not only did the research team make this significant
discovery about the T-cells’ location, they also
found that the CD8αα+ T-cells are programmed to
remain in the skin surrounding the genitals at all
times – making them resident memory T-cells. The
cells’ long-term persistence may explain why
patients have asymptomatic recurrences of genital
herpes, because the cells are constantly doing
“immune surveillance” – always working to find and
destroy HSV-2.
“The real implication here is that the way herpes
seems to act is that the virus is actually
reactivating very frequently,” Corey said. “The
human immune response is containing it most of the
time.”
Researchers had originally estimated that herpes
reactivated once a month, but the discovery of these
ever-present T-cells led Corey and his team to
believe the virus actually reactivates once a week
or every few days. So when herpes lesions occur, it
is because there were not enough CD8αα+ T-cells to
suppress the outbreak, Corey said.
CD8αα+ T-cells were previously known to exist in the
gut mucosa, but most of the research on CD8+ T-cells
focused on studying them in blood circulation.
Corey and his team were the first to find the
phenotype of CD8αα+ T-cells to persist in the skin.
He said that a potential herpes vaccine would focus
on increasing these cells in the immune system.
“It gives us a marker by which one can test
vaccines,” Corey said. “A vaccine that will
increase the number or function of these cells would
be one you would want to develop. I don’t think
there would be any side effects.”
The vaccine could potentially stop individuals from
experiencing outbreaks – the times when a person is
most contagious. Generally, a person can only
contract HSV-2 infections during sexual intercourse
with an infected individual; however, transmission
can still occur when the infected individual does
not have a visible sore.
According to the Centers for Disease Control and
Prevention, 776,000 people in the United States are
infected with herpes each year, and one out of six
people between the ages of 14 and 49 have genital
HSV-2 infection. While this vaccine would not cure
those of HSV-2, it could ultimately help stop the
spread of this very prevalent STI.
“We think it’s possible to contain,”
Corey said. “It’s a ‘clinical cure.’”
Researchers discover gene that suppresses
Herpesviruses: TLKs
Tousled-like kinases - TLKs - play a key role in
the suppression and activation of Herpesviruses.
Kaposi’s
sarcoma-associated
herpesvirus (KSHV)
and Epstein-Barr
virus (EBV) hide
within the
worldwide human
population.
While dormant in
the vast
majority of
those infected,
these active
herpesviruses
can develop into
several forms of
cancer. In an
effort to
understand and
eventually
develop
treatments for
these viruses,
researchers at
the University
of North
Carolina have
identified a
family of human
genes known as
Tousled-like
kinases (TLKs)
that play a key
role in the
suppression and
activation of
these viruses.
In a paper
published by
Cell Host and
Microbe on Feb.
13, 2013, a
research team
led by Blossom
Damania, PhD, of
the Department
of Microbiology
and Immunology
and member of
the UNC
Lineberger
Comprehensive
Cancer Center,
found that
suppressing the
TLK enzyme
causes the
activation of
the lytic cycle
of both EBV and
KSHV. During
this active
phase, these
viruses begin to
spread and
replicate, and
become
vulnerable to
anti-viral
treatments.
“When TLK is
present, these
viruses stay
latent, but when
it is absent,
these viruses
can replicate”
says Damania.
Patrick Dillon,
a postdoctoral
fellow in
Damania’s lab,
led the study.
Other co-authors
included UNC
Lineberger
members Drs.
Dirk Dittmer,
Nancy Raab-Traub
and Gary
Johnson.
KSHV and EBV are
blood-borne
viruses that
remain dormant
in more than 95
percent of those
infected, making
treatment of
these viruses
difficult. Both
viruses are
associated with
a number of
different
lymphomas,
sarcomas, and
carcinomas, and
many patients
with suppressed
immune systems
are at risk for
these
virus-associated
cancers.
“The dormant
state of these
viruses is what
makes it so hard
to treat these
infections and
the cancers
associated with
these
infections,”
says Damania.
Researchers have
known that
stimuli such as
stress can
activate the
virus from
dormancy, but
they do not
understand the
molecular basis
of the viral
activation
cycle. With the
discovery of the
link between
these viruses
and TLKs, Dr.
Damania said
that researchers
can begin to
look for the
molecular
actions
triggered by
events like
stress, and how
they lead to the
suppression of
the TLK enzymes.
“What exactly is
stress at a
molecular level?
We don’t really
understand it
fully,” says
Damania.
With the
discovery that
TLKs suppresses
these viruses,
Damania said
that the
proteins can now
be investigated
as a possible
drug target for
these
virus-associated
cancers. In its
normal function
in the cell,
TLKs play a role
in the
maintenance of
the genome,
repairing DNA
and the assembly
of the
chromatin, but
there is a lot
more to learn
about the
function of the
TLKs, says
Damania. One
avenue of her
lab’s future
research will
investigate how
TLKs function in
absence of the
virus.
“If we prevent
this protein
from
functioning, and
we combine this
with a drug that
inhibits viral
replication,
then we could
have a target to
cure the cell of
the virus. If
the virus isn’t
there, the
viral-associated
cancers aren’t
present,” says
Damania.
Straitjacket drug halts herpes
virus's escape stunt
"You don't
ever get the virus coming back,"
As anyone who suffers
from recurrent cold sores knows, herpes
is a master escapist. This family of
viruses – including strains that cause
lesions on the genitals, infectious
mononucleosis (glandular fever) and, in
some cases, blindness and birth defects
– is able to wriggle free of the body's
defences, reactivating after lying
dormant for long periods. Now a new drug
that denies the virus its means of
escape could lead to treatments that
keep herpes locked up for good.
When the virus infects
cells, the body defends itself by
wrapping up the viral genome in a
structure that blocks its genes from
being expressed. The virus can escape
this straitjacket, though, by hijacking
some of the cell's own enzymes to unwrap
itself. Once freed, the virus takes hold
and spreads.
Thomas Kristie at the National
Institute of Allergy and Infectious
Diseases in Bethesda, Maryland, and
colleagues have developed a drug that
inhibits the enzymes the virus uses to
free itself – stopping it from escaping.
"The virus becomes silent," says
Kristie.
The team tested their
treatment on mice infected with herpes
simplex type 1, which causes lesions on
the mouth and eye.
About a month after
infection, once the virus had entered
its dormant stage, the researchers
removed neurons from a brain region
behind the eye where herpes lurks, and
cultured the cells. They found they were
unable to reactivate the virus. "You
don't ever get the virus coming back,"
says Kristie. The drug also appears to
limit the spread of the initial
infection.
New drug arena
This approach of
inhibiting the enzyme that the virus
hijacks could lead to new treatments
that shut down the herpes family of
viruses at an early stage of infection.
It might even work on other viruses that
take over cells in a similar way, such
as HIV. "This could open up a new arena
of antiviral drugs that hit a number of
viruses," says Kristie.
"It's neat that they
got such a potent effect," says
Robert White at Imperial College
London, UK, who was not involved in the
study. But more work is needed to
investigate possible side effects, he
says, since the drug is likely to be
knocking out more than just the host
enzymes used by the virus. "It's a bit
of a sledgehammer."
A vaccine for herpes? Researchers discover
immune cells that suppress HSV-2 infection | Fox
News