close

Вход

Забыли?

вход по аккаунту

?

Overview The biology of varicella-zoster virus infection.

код для вставкиСкачать
Overview: The Biology of
Varicella-Zoster Virus Infection
Stephen E. Straus, MD
Vaticella-zoster virus infection is manifested initially as chickenpox. The virus persists for life in sensory nerve ganglia,
from which it reactivates in many people to cause zoster. Among the many recognized complications of these infections,
post-zoster neuralgia is the most frequently debilitating. The molecular events of virus replication, latency, and
reactivation, and the pathogenesis of post-zoster neuralgia, are incompletely understood and inadequately addressed
by current therapeutic strategies.
Straus SE. Overview: the biology of varicella-zoster virus infection. Ann Neurol 1994;35:S4-S8
virus, as evidenced both by circulating virus-specific
antibodies and the known lifetime carriage of the virus
in a latent state. VZV is highly contagious. Over 80%
of susceptible household contacts acquire the virus.
Transmission is largely through inhalation of infectious
aerosols, but direct contact with active varicella or 20ster lesions also leads to infection.
Within days of infection, the virus has completed its
first rounds of replication near sites of inoculation, and
waves of viremia and visceral infection ensue. Ten to
21 days after infection, replication of virus in skin,
cleavage across epidermal planes, and infusion of an
inflammatory exudate create the classic vesicular exanthem of varicella.
Varicella (chickenpox) is an annoying infection that
can lead to a vast range of local or systemic complications that arise from replication of virus in vital viscera
including the lungs, the liver, and the central nervous
system. The healthy child has little risk of these compli-
cations; they are more the domain of individuals with
impaired cellular immune responses to the viruses.
The purpose of this workshop, though, is to focus
on aspects of zoster rather than varicella. Zoster (shingles) is the clinical expression of virus that had lain
dormant in sensory ganglia from the time of varicella
and now reactivates focally. The epidemiological data
that still serve us best, although 30 years old, inform
us that zoster is an infection whose likelihood increases
directly in proportion to the age of the individual and
inversely with the individual's immune competence r4,
5}. Zoster arises at any age. We tend to think of zoster
as something that our parents get in their declining
years, yet there are infants who develop shingles.
This infection carries its own wide range of complications. One such complication is exhibited in Figure
1. This individual with V2 trigeminal infection developed the Ramsey-Hunt syndrome. He cannot fully
close his eye or grimace properly.
The ability of zoster to injure components of the
nervous system is one underrecognized aspect of this
infection. Another that distinguishes zoster from herpes simplex virus infection is the ability of VZV to
burrow deeply into the dermis to leave scars and other
more serious manifestations of infarctive necrosis of
tissues. VZV produces a spotty angiitis of sufficient
intensity to cause ischemia. Figure 2 shows a woman
with lymphoma whose case history was summarized
previously [GI. Zoster of her V1 and V2 dermatomes
was associated with not only a disfiguring dermal eschar, but also infarction of the maxillary artery and loss
of all the teeth served by it on that side. Moreover,
she had infarction of a division of the middle cerebral
artery, resulting in hemiparesis. Figure 2B shows the
From the Laboratory of Clinical Investigation, National Institute of
Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD.
Address correspondence to Dr Straus, Laborarory of Clinical Investigation, Building 10, Room 1lN228, National Institutes of Health,
9000 Rockville Pike, Bechesda, MD 20892.
The present workshop is designed to summarize the
recent developments in varicella-zoster virus (VZV)
biology and disease, particularly as they provide new
insights into the treatment and prevention of infection
and its painful sequelae. What follows is an overarching
introduction to the problem of VZV infection itself,
with an emphasis on the biology of the virus. The pace
at which there has been development in these areas is
impressive. It is a testimony to those of us who can
fantasize about research medicine and particularly to
those who can bring things to reality.
The Problem
VZV is a ubiquitous infectious agent {1-3]. At least
95% of the US adult population is infected with the
s4
peated and prolonged exposure of the patient to
acyclovir selects for drug-resistant strains that can only
be cleared with foscarnet [9}.
Major failures in our thinking about zoster have
been insufficient appreciation of its most common and
important complication-namely, the pain associated
with and following the infection-and inadequate development of any real understanding of its pathogenesis. In the late 1950s, we were taught that the likelihood of acute pain and of chronic post-zoster neuralgia
increases markedly with advancing age (Fig 3) [lo].
Although more recent studies have not suggested quite
this high a rate of pain, post-zoster neuralgia is a daunting challenge that is still insufficiently met by the available antiviral drugs. Later in this workshop, we will
hear that high-dose oral acyclovir can reduce the rate
of post-zoster neuralgia in elderly immunocompetent
patients. These data are from but one of the several
studies on acyclovir Ell]. A salutary effect on chronic
pain is not a consistent finding and, even if it were,
should give us little pause for complacency, for even
with acyclovir, the duration and rate of pain are excessive and, frankly, unacceptable.
Fig I . The Ramsey-Hunt syndrome. A patient with left-sided
facial zoster (A) exhibits facial and ocular measles (B).
appearance of the woman several months h e r , with
temporal wasting, tremendous scarring, atrophy, and
blindness on the affected side, all due to infarction.
The past 20 years of work by Richard Whitley, and
the Collaborative Antiviral Study Group that he chairs,
has taught us to focus on the spectrum of zoster as it
is manifested in the compromised host with dissemination of infection, in all too many instances, to the lungs,
the liver, the central nervous system, and other tissues
[7, 8}. In the last few years, a whole new spectrum of
zoster was revealed through the emergence of acquired
immunodeficiency syndrome (AIDS). Zoster, which is
classically an acute evanescent infection that rarely recurs, now exhibits its sinister potential for recurrent
and chronic infection. In late stages of AIDS, the re-
Virus Biology
While learning something of the clinical spectrum, epidemiology, and treatment of zoster, we have managed
to learn a good deal about the virological underpinnings of this infection {Z]. The molecular tools available are so sophisticated today that we are, in fact,
making easier progress in this area than in the other,
more complex areas summarized above. When Hay,
Ruyechan, and I started collaborating on studies of
VZV a dozen years ago, we considered ourselves fortunate to be able to grow the virus and recover DNA
from it for analysis. With Davison’s seminal work of 8
years ago on the entire sequence of the virus, we had
set before us the code of the 69 genes of the virus that
endow it with its properties, and we have learned a bit
about gene regulation and replication of the virus [12}.
Some of this has been by the fortuitous analogy to
what was learned more readily of the herpes simplex
virus.
VZV replication is dependent on a cascade of gene
expression that is triggered by a number of transregulatory genes. Data from Ostrove, Cohen, Rentier, Hay,
and many others tell us that, as enumerated from the
left to right ends of the viral genome, genes 4, 10, 61,
62, and 63 all participate in dictating and refining the
pace of expression of the virus as a whole [13]. Most
immediately, these genes induce the expression of a
subsequent set of genes which encode the enzymes
necessary for viral D N A replication. These, in turn,
set the stage for the production, trimming, and assembly of structural proteins into a new, infectious progeny
virion.
Straus: VZV Infections
S5
Fig 2. Severe necrotizing left-sidedfacial zoster in a womm
with lymphoma (A) results 10 weekJ kzter in scarring and atrophy of the temporal mascle (Bi. (Reproducedfrom Wright et a1
{6) with pemzission.)
It is the enzymes of this virus that provided the first
meaningful targets for antiviral drugs. The existing
drugs in the clinic-and most of rhose in the development pipeline-are activated by the viral deoxypyrimidine kinase and inhibit the viral DNA polymerase.
This mechanism defines the activity of acyclovir, ganciclovir, newer drugs such as the valine ester prodrug
of acyclovir, famciclovir and its active metabolite penciclovir, and sorivudine. This last drug, also known as
bromovinylarauracil, or BVaraU for short, has superior
pharmacological properties and stunning in vitro activity. Preliminary data suggest that 40 mg of sorivudine
given once daily may be as effective as 800 mg of
acyclovir given five times daily in the treatment of
VZV infections 1111. Now that we have extremely
potent drugs, we have the opportunity to learn
whether adequate and early treatment of zoster itself
is sufficient to prevent post-zoster neuralgia. It may
not be.
The capacity of this virus to reactivate and cause
zoster rests on its ability to persist in the body for life.
Unfortunately, we understand only the barest rudi-
S6 Annals of Neurology Supplement to Volume 35, 1994
1
pain < 1 month
pain > 1 month
n
n
r
C20 20-29 30-39 40-49 50-59 60-69 270
age groups (yrs)
Fig 3 . The prevalence and duration of pain among 916 $atients with zoster. by age. (Modifiedfmnz de Moragas and Kierland {lo}and reproduced from Straus et ai { I } with permission.)
Fig 4. Viral cytopathic changes in a human senso? ganglion associated with zoster (courtesy of Micbael Oxman). Numerous intranucleur inclusions are seen in satellite and interstitial cell1
surrounding a large neuron. iReproduced from Meier and
Straus 114) with permission.)
ments by which this process occurs [14}. We know
where the virus persists, we have some idea of how it
gets there, and we know a little bit about the state of
the latent genome, but we know very little about why
this virus reactivates infrequently compared to herpes
simplex virus. We do not know what triggers VZV
reactivation; we have a better understanding that ultraviolet light, local trauma, and other systemic irritants
can trigger herpes simplex virus reactivation. We do
not know what role the immune system plays in sustaining virus latency, although it is likely that there is
such a role because cellular immune impairment increases the likelihood of reactivation. We are not certain what happens to cells in which the virus persists
and reactivates, although they may be severely damaged and contribute, in this way, to the development
of pain. Other speakers at this workshop address this
latter issue more fully.
By analogy to herpes simplex virus, we initially had
reason to believe that the virus persists in sensory ganglia. Very good clinical observations of the past half
century-and hypotheses formed from them-have
supported this notion, but it has only been the last
several years in which direct proof of this concept was
obtained.
In situ hybridization studies reported by Croen several years ago taught us that in varicella, one can detect
evidence of viral replication in a large number of both
neuronal and nonneuronal cells of the human trigeminal ganglion {151. By spread either up the neuraxis
from the periphery or hematogenously, the virus arrives in large amounts to infect a spectrum of cellular
types within the ganglion. It is less fully settled, however, as to where the virus persists once that acute
infection has subsided.
We know from the work of Mahalingham and colleagues that the viral genome can be detected in virtually every trigeminal ganglion of individuals who are
seropositive for VZV [161. His polymerase chain reaction studies showed a lower frequency of infection in
thoracic ganglia. The genome resides in these ganglia
in very low copy number, but we have reason to believe that some of the resident genes are active and
being expressed during latency.
The cellular locus of latency is controversial. We
know from parallel studies that herpes simplex virus
persists in human neurons, about 0.1% of which can
be shown to contain large amounts of a single latencyassociated viral RNA, while VZV seems to persist in
the nonneuronal satellite cells [ 151. More recently,
Meier and colleagues-in a very arduous series of experiments involving about 200 human trigeminal ganglia-established by Northern hybridization that VZV
genes 29 and 62 are expressed during latency [17).
Gene 29 participates in viral DNA replication, and
gene 62 encodes the critical transregulatory protein of
the virus. How the expression of these and perhaps a
few other genes contributes together to perpetuating
the virus’s foothold in the nervous system is not
known; nonetheless, we have reason to believe that
zoster involves an explosive and destructive spread of
virus across segments of sensory ganglia including numerous satellite cells. We know this from careful examination of tissue photomicrographs like those kindly
provided by Michael Oxman (Fig 4). Here, the ganglion of a patient who succumbed with zoster is seen
to possess numerous cells bearing Cowdry type A inclusions, both within neurons and in the satellite cells
surrounding them. This is not the pathology of herpes
simplex virus infection. The destructive replication of
VZV within the ganglia provides the fertile ground on
which its neurological complications and pain are
borne. By attention to the details of this process, we
will effect better strategies for prevention and treatment of post-zoster neuralgia.
Ms Brenda Rae Marshall provided expert editorial assistance in the
preparation of this manuscript.
Straus: VZV Infections
S7
References
1. Straus SE, Ostrove JM, Inchauspk, et al. Varicella-zoster virus
infections: biology, natural history, treatment, and prevention.
Ann Intern Med 1988;108:221-237
2. Gelb LD. Varicella-zoster virus. In: Fields BN, Knipe DIM, Chanock RM, et al, eds. Fields virology. 2nd ed. New York: Raven,
1990:2011-2054
3. Gershon AA, ed. The First International Conference on the
Varicella-Zoster Virus. J Infect Dis 1992;66(suppl l):Sl-S68
4. Hope-Simpson RE. The nature of herpes zoster: a long-term
study and a new hypothesis. Proc R SOCMed 1965;58:9-20
3. Ragozzino MW, Melton LJ 111, Kurland LT, et al. Populationbased study of herpes zoster and its sequelae. Medicine (Baltimore) 1982;61:310-3 16
6. Wright WE, Davis ML, Geffen DB, et al. Alveolar bone necrosis
and tooth loss, a rare complication associated with herpes zoster
infection of the fifth cranial nerve. Oral Surg Oral Med Oral
Pathol 1983;58:39-46
7. Whitley RJ, Ch'ien LT, D o h R, et al. Adenine arabinoside
therapy of herpes zoster in the immunosuppressed: NIAID collaborative antiviral study. N Engl J Med 1976;294:1193-1109
8. Whitley RJ, Gnann JM Jr, Hinthorn D, et al. Disseminated
herpes zoster in the immunocompromised host: a comparative
trial of acyclovir and vidarabine. J Infect Dis 1992;165:450-455
9. Jacobson MA, Beger TG, Fikrig S, er al. Acyclovir-resistant
S8 Annals of Neurology Supplement to Volume 35, 1994
10.
11.
12.
13.
14.
15.
16.
17.
varicella-zoster virus infection after chronic oral acyclovir therapy in patients with the acquired immunodeficiency syndrome
(AIDS). Ann Intern Med 1990;112:187-191
de Moragas JM, Kierland RR. The outcome o# patients with
herpes zuster. Arch Dermatol 1957;75:193-196
Whitley RJ, Straus SE. Therapy for varicella-zoster virus infections: where do we stand! Infect Dis Clin Pract 1993;2:
100-108
Davison AJ, ScottJE. The complete DNA sequence ofvaricellazoster virus. J Gen Virol 1986;67:1759-1816
Ostrove JM. Molecular biology of varicella-zoster virus. Adv
Virus Res 1990;38:45-33
Meier JL, Straus SE. Comparative biology of latent varicellazoster virus and herpes simplex virus infections. J Infect Dis
1992;166(s~ppl1):s1 3 4 2 3
Croen KD, Ostrove JM, Dragovic LJ, Straus SE. Patterns of
gene expression and sites of latency in human trigeminal nerve
ganglia are different for varicella-zoster and herpes simplex virus. Proc Natl Acad Sci USA 1988;85:9773-9777
Mahalingham R, Wellish M, Wolf W, et al. Latent varicellazoster viral DNA in human trigeminal and tunacic ganglia. N
Engl J Med 1990;323:627-631
Mcier JL, Holman RP, Croen KD, et al. Varicella-zoster virus
transcription in human trigeminal ganglia. Virology 1993;193:
193-200
Документ
Категория
Без категории
Просмотров
3
Размер файла
1 153 Кб
Теги
overview, zostera, varicella, virus, biologya, infectious
1/--страниц
Пожаловаться на содержимое документа