Research Reveals How Herpes Simplex Virus Can Be Kept Asleep Inside Its
Harboring Cell

11/15/05 -- The ubiquitous herpes simplex virus-1 (HSV-1), which takes
up permanent residence inside sensory nerve cells where it hibernates
before plotting its next infection, could be kept in deep slumber with
the aid of a specific immune system cell, suggests new research.
Reporting in this month's lead article in the journal Immunity,
University of Pittsburgh researchers reveal how this cell helps
maintain latency of the virus, keeping it fast asleep inside the cell.
Their findings have implications for the development of therapies that
would prevent recurrent infections.

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By age 40, most adults have been exposed to HSV-1, for many the source
of painful and unsightly cold sores that can appear smack on the lips
at the most inopportune times. For some 500,000 people, HSV-1 manifests
in the corneas, giving rise to repeated episodes of blurred vision,
each infection leaving behind another layer of scar tissue that over
time can lead to total blindness.

The only way to stop the cycle of this highly contagious virus is to
prevent its replication inside the sensory neurons that unwittingly
harbor HSV-1. According to the new research, this might best be
achieved by taking advantage of a unique relationship between these
sensory neurons and their special partner, the CD8+ T cell.

This specific immune cell, in essence, has the ability to keep HSV-1 in
a dormant state through a "cook-to-order" method. Using a mouse model
of ocular HSV-1, the kind that infects the cornea, the authors made the
interesting discovery that two distinct types of sensory neurons play
host to the virus. Moreover, they found that CD8+ T cells are able to
cater to the needs of either one.

Robert L. Hendricks, Ph.D., a professor of ophthalmology at the
University of Pittsburgh School of Medicine, and his team had
previously observed that CD8+ T cells hone to neurons harboring latent
virus, their presence somehow preventing virus replication. In these
latest studies, they sought to understand how this was accomplished.

"We had assumed the interaction between CD8+ T cells and sensory
neurons containing latent HSV-1 was complex, but we were quite
surprised to learn there are two kinds of these sensory neurons,
existing in nearly equal number, and that depending on the neuron type,
CD8+ T cells are capable of employing either of two different
mechanisms that keeps the virus at bay," said Dr. Hendricks, who holds
secondary appointments as professor in the departments of molecular
genetics and biochemistry and immunology at the Pitt School of
Medicine. "Finding a way to harness this immunological process during
times of stress, when reactivation of HSV-1 is most likely to occur,
will be key to developing a therapeutic approach, such as a vaccine,"
Dr. Hendricks added.

According to the published report, CD8+ T cells are able to distinguish
between the needs of the two neurons by their cell-surface markings.
One of the neurons is adorned with two distinctive molecules that make
clear its preference for gamma interferon, proteins with antiviral
qualities that are produced by CD8+ T cells. Of the two markings, one
is a specific receptor for gamma interferon, the key required for its
signaling inside the cell; while the other cell-surface molecule serves
as a plug, keeping CD8+ T cells from offering their other menu item,
lytic granules. The second neuron type has no special trimming ? no
receptor for gamma interferon and no plug to keep the lytic granules
out. Indeed, lytic granules are what these particular neurons require
to keep HSV-1 in hibernation.

Interestingly, these lytic granules, a form of ammunition T cells
usually engage to kill unwanted invaders, spare these neurons. This is
important because neurons are incapable of regenerating, explains Dr.
Hendricks and the study's first author, Kartik Prabhakaran, a
University of Pittsburgh School of Medicine M.D.-Ph.D. student. If the
lytic granules were to cause a cell's death, the consequences would be
especially devastating for people with ocular HSV-1.

There's much more to understand about the intricate relationship
involving these immune cells and sensory neurons ? an understanding
that might also have implications for the treatment of other diseases,
such as muscular sclerosis. But one question emerges as perhaps the
most important. Future studies, the authors say, must focus on
maintaining the integrity of the cellular relationship in times of
stress, when HSV-1 is most likely to be replicated and escape unnoticed
by CD8+ T cells that have been weakened by hormones released to cope
with the stress.

HSV-1 works by infecting epithelial cells, a cell type that forms the
outer layer, or epithelium, of tissues and organs, including the skin.
The virus favors the epithelial cells around the mouth, nose and
cornea, although cells lining genitalia may also be infected. Once
embedded in the epithelium, HSV-1 has little difficulty finding the tip
of a sensory neuron's axon, a nerve cell's long extension by which
signals travel. The axon is the virus's direct route to the neuron cell
body and the cell's nucleus, where it takes up residence and remains in
latent form until reactivation. After HSV-1 replicates in the cell
nucleus, it again finds convenient passage along the neuron's axon,
which puts the virus within easy reach of epithelial cells to infect
anew. Such is the cycle of HSV-1 reinfection, with sensory neurons
literally serving as the loop.

Why some individuals who carry the virus never suffer even a random
cold sore while others are forever susceptible to repeated bouts is not
well understood. The same is true for those affected by the ocular
form, although frequent corneal infections can be much more serious.
While antiviral medications can help relieve the primary symptom,
blurred vision, they don't prevent reinfection. Nor do they stop scar
tissue formation caused by the immune system's inflammatory response
and the complications that ensue. HSV-1 is the most frequent infectious
cause of blindness and a leading indication for corneal
transplantation.

To study the virus, the authors developed an animal model of ocular
HSV-1. To observe viral gene expression during latent infections, they
used recombinant viruses, prepared in the laboratory of co-author Paul
K. Kinchington, Ph.D., that express a fluorescent protein when certain
viral genes are active. The results reported in the current paper were
obtained in studies of mouse sensory neurons that were analyzed in
culture. Future research will aim to replicate these findings in the
live animal.

Source: University of Pittsburgh Medical Center

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