Download Pathogenesis, latency and reactivation of infections by

Rev. sci. tech. Off. int. Epiz., 1986, 5 (4), 809-819.
Pathogenesis, latency and reactivation
of infections by herpesviruses
E. THIRY, J. DUBUISSON and P.-P. PASTORET*
Summary: After a brief review of the pathogenesis
of herpesvirus
infections,
the essential aspects of latency are presented: the sites, the state and control of
latency. The stimuli of reactivation are reviewed and the putative
mechanisms
leading ot reactivation are discussed. Re-excretion,
which is the direct consequence of reactivation,
is also detailed. Latency has a great
epizootiological
significance, mainly because of re-excretion. Re-excretion
of virus by latently
infected carriers, without any clinical sign, ensures the silent transmission
of
virus to susceptible in-contact animals. New prophylactic
measures must consider not only the prevention of the clinical effects of infection with a virulent
virus, but also the prevention
of
re-excretion.
K E Y W O R D S : Bovine herpesvirus - Cattle diseases - Herpesviridae - Latent
infection - Pathogenesis - Viral diseases.
INTRODUCTION
Herpesvirus infections of domestic animals are of great importance in livestock
and poultry production, especially because herpesviruses have developed sophistica­
ted strategies to persist in susceptible populations of restricted size. Latency is the
property shared by all herpesviruses which allows them to persist indefinitely in
their host after a primary or secondary infection (45). The mechanisms of establish­
ment and maintenance of latency are not yet fully elucidated, but molecular studies
are in progress for several herpesvirus models and recent data suggest that latency is
under the control of viral latency genes. New hypotheses are available concerning
the coding regions involved in the establishment and maintenance of latency and
for the level of genome expression during latency.
Nevertheless, these mechanisms may differ according to the herpesvirus studied
and the term "latency" has certainly not the same meaning for each one. Differen­
ces between herpesviruses are indeed observed in the site of latency, the state of the
latent viral genome, the ability to furnish in vitro models of latency, the frequency
of reactivation and the stimuli able to induce it. Moreover, virus-host relationships
must be taken into account: the behaviour of the same herpesvirus may differ
depending on the animal species or the cells infected by the virus.
This paper deals with general and comparative aspects of pathogenesis, latency,
reactivation and re-excretion of animal herpesviruses. Emphasis will be given to
mechanisms which allow herpesviruses to escape the measures, mainly vaccination
and eradication, used until now to control their propagation (40).
* Department of Virology and Viral Diseases, Faculty of Veterinary Medicine, University of Liège,
45, rue des Vétérinaires, B-1070 Brussels, Belgium.
— 810 —
PATHOGENESIS OF HERPESVIRUS INFECTIONS
The range of diseases caused by herpesvirus infections is quite large. Moreover,
the same virus can provoke different diseases, depending on the viral strain, the age
of the animal or the route of infection. Bovine herpesvirus 1 (BHV-1) and Suid
herpesvirus 1 (SHV-1) are good examples: BHV-1 infection of cattle causes rhinotracheitis, vulvovaginitis, conjunctivitis, abortion in pregnant cows, encephalitis in
young calves, metritis; BHV-1 is also associated with enteritis and mastitis (44).
SHV-1 infection of pigs is followed by abortion in pregnant sows, by septicaemia in
neonates, by encephalomyelitis in piglets or by respiratory diseases in young pigs
and adults (3).
In domestic animals, clinical disease is usually produced following a primary
infection; recrudescent disease, i.e. caused by a reactivated virus, seems to be rare.
The situation differs in humans: labial and genital recrudescent lesions are com­
monly observed in humans infected with herpes simplex virus type 1 and 2 (HSV 1
and 2), even in the presence of a high level of specific immunity (34). Shingles is a
painful expression of reactivation of varicella-zoster virus, another human herpes­
virus.
Virulence is a genetically controlled property and regions of the viral genome
carrying virulence markers are beginning to be identified, especially for HSV and
SHV-1. Thymidine kinase (TK) gene was the first gene of virulence unambiguously
demonstrated. TK-negative mutants are shown to be avirulent (4, 22, 23, 31), but
markers of virulence are also found in other parts of the genome (5, 27, 50, 64).
Proteins coded by these regions remain to be studied. The knowledge of the geno­
mic regions bearing virulence markers will lead, in the near future, to building spe­
cifically avirulent deletion mutants designed as artificially attenuated vaccine
strains.
LATENCY
Latency is defined as the silent persistence of the virus in the body, not detecta­
ble by conventional virological procedures (44). Infectious virus is only recovered
from latently infected organs by prolonged culture of organ cells or co-culture of
these cells with susceptible cells (30, 47). Therefore, no infectious virus is reisolated
in cell cultures inoculated with a triturated organ latently infected.
Establishment of latency
Expression of some viral genes is required for the establishment of the virus in a
latent state. The TK gene was the first gene of latency recognized, but this point is
conflicting: even low TK-producing mutants of HSV-1 remain latent (14). TK acti­
vity is not absolutely required for the multiplication of HSV in the trigeminal gan­
glion (10). Moreover, Kit et al. have recently reported the successful establishment
of TK-negative mutants of BHV-1 in a latent state (23).
The multiplication of herpesvirus is not absolutely necessary for the establish­
ment of latency. Thermosensitive mutants, which are unable to multiply in the
mouse, may persist in a latent form (26). Nevertheless, virus multiplication greatly
increases the amount of viruses within the body and therefore the possibility to pro­
duce latency.
— 811
The sites of latency
Three sites of latency are described for the herpesviruses: nervous, epithelial and
lymphoid sites. Epstein-Barr virus (EBV; human herpesvirus 4) persists in a latent
state in peripheral B-lymphocytes of infected humans (36). The virus, as well as
Marek's disease virus (MDV; Gallid herpesvirus 1) is a member of the Gammaherpesvirinae and lymphoid latency is a property of this sub-family (49). A group of
bovine herpesviruses, tentatively classified as bovid herpesvirus 4 by Ludwig (29),
which comprises a cluster of respiratory and genital isolates (strain DN599, Movar
33/63, etc.), seems also to establish lymphoid latency in cattle (38) and, in experi­
mentally infected rabbits, monocytes could be a site of latency (39). Other characte­
ristics (growth in cell culture, electron microscopy of infected cells) have led to clas­
sify them as bovine cytomegalovirus (60). Murine cytomegalovirus, a true member
of the Betaherpesvirinae, is able to establish latency in salivary gland cells and in
spleen lymphocytes (48). Alphaherpesvirinae possess a nervous site of latency: the
nervous ganglions and especially the trigeminal one (6, 49). Nevertheless, skin is an
important site for bovine herpesvirus 2 (BHV-2) latency (32, 57) even if latency in
the nervous system has also been described (7). Moreover, HSV establishes latency
in the skin of the guinea pig and mouse (19, 58). An epithelial site of latency must
therefore be carefully considered for other Alphaherpesvirinae.
The state of latency
Two states of latency are classically described (6): (a) the dynamic state: virus
multiplication still occurs in latently infected cells, so that, at any time, the cells
contain a reduced amount of infectious virus; (b) the static state: no productive
infection occurs in latently infected cells where the genetic information of virus is at
least retained, since infectious virus can be recovered by in vitro cultivation of these
cells.
The second hypothesis is the most probable (6, 66). Indeed, latency can be estab­
lished by thermosensitive mutants which are unable to multiply in the mouse (26).
The state of the latent viral genome may vary: integration into cellular DNA of
cytomegalovirus genome (11) or presence in an episomic form. The two forms can
coexist, as described in vitro for EBV (2, 25) and MDV (55). In several systems, it is
demonstrated that certain parts of the genome are transcribed during latency (6;
Rock D. L., Mayfield J. and Osorio F. A., personal communication; Rziha H.-J.,
Ohlinger V., Mettenleiter T.C., Bandtlow I. and Falser N., personal communication).
Latency is sometimes defined as a transcriptional block, but it must be partial (37).
The regions of the genome transcriptionally active during latency could support the
genes which are involved in the maintenance of latency. The level of expression on
the viral genome is different depending on the site of latency. When latency occurs in
a neuronal site, and this is the case at least for Alphaherpesvirinae, transcription is
very reduced. However, if the site of latency is the lymphocyte, viral genome is more
expressed and specific viral antigens are present on the surface of persistently infected
lymphoblastoid cells (17).
In vitro models of latency have been described for HSV. Inhibition of virus multi­
plication and incubation at supraoptimal temperature are classically used to establish
persistent infection in vitro (54).
Since our knowledge of natural latency is very limited, it is impossible to assess
the relevance of such in vitro models.
— 812 —
Control of latency
The control of latency and the mechanisms leading to reactivation are closely
related since these mechanisms provide a counter-order to the order of maintaining
the latent state.
Virus could be maintained in a latent state either by a control of the specific
immune response or by a biological relationship between virus and latently infected
cells. A better knowledge of the genes involved in latency will contribute to the
study of such relationship.
The first hypothesis, control by the immune response, supposes at least the
expression of viral antigens on the membrane of latently infected cells. It seems that
Alphaherpesvirinae do not express antigens in latently infected cells. Only an imme­
diate early polypeptide (ICP4) of HSV has been identified in the nucleus of latently
infected neurons (15). On the other hand, Gammaherpesvirinae, like EBV, do
express viral antigens on the surface of latently infected lymphocytes and these cells
are effectively destroyed by immunocytolysis (16); nor does the immune response
really control latency in the latter case. The putative involvement of the immune
response in the control of latency will also be discussed in the section dealing with
stimuli of reactivation.
REACTIVATION
Reactivation is defined as the appearance of infectious virus at the site of
latency. Re-excretion is defined by the presence of infectious or non-infectious virus
in peripheral tissues and organs, followed by its excretion outside the body. The ter­
minology usually adopted for HSV infection is:
Recurrence is the appearance of infectious virus in the periphery without any
clinical lesion; recrudescence or recrudescent disease consists of clinical lesions in
peripheral tissues, produced by a recurrent virus (6).
Reactivation in itself is very difficult to demonstrate. The only way is to directly
investigate the site of latency and to check it for the reappearance of virus multipli­
cation. More often, reactivation is studied by its direct consequences: re-excretion
and booster immune effect.
Stimuli of reactivation
Several stimuli of reactivation have been recorded and they may differ from one
herpesvirus to another. The frequency of reactivation is so high in certain models
(e.g. guinea pigs infected with HSV) that it is impossible to identify a stimulus of
reactivation because one cannot clearly distinguish between spontaneous and pro­
voked reactivation. On the other hand, the definition of spontaneous reactivation is
not obvious: it could be caused by an endogenous condition of the latently infected
animal or by a modification of the latent virus-infected cell relationship, at a cellu­
lar level (24).
Nevertheless, stimuli of reactivation have been unambiguously identified in
most herpesvirus infections. They include stressful conditions, parturition, trans­
port, superinfection by another virus (63), re-housing (13), local irritation of the
skin (18) and cyclophosphamide treatment (6, 65). The most important experimen­
tal stimulus of reactivation is the injection of glucocorticoids since it reactivates
— 813 —
several herpesviruses of veterinary importance: Bovine herpesvirus 1 (BHV-1) (59),
Bovine herpesvirus 2 (BHV-2) (57), Feline herpesvirus-1 (12), SHV-1 (33) and,
recently, Equid herpesvirus 1, which has been successfully reactivated and reexcreted by latently infected ponies (9).
The mechanisms of reactivation
The mechanisms of reactivation are related to the factors involved in the control
of latency. Three hypotheses must be considered: reactivation of latent herpesvirus
could be induced either by immunodepression, or by a direct effect of the stimulus
on the latently infected cells or by a combination of these two mechanisms. The two
mechanisms can be illustrated by the effect of injection of glucocorticoids. Gluco­
corticoids could act either by their known immunodepressive properties (51), or by a
direct effect on the latently infected cell (41). The second hypothesis is supported by
the fact that glucocorticoids enter the cell, are coupled with a vector protein and
can selectively induce transcription of certain parts of the genome. In another
family of viruses, the Retroviridae, the direct effect of glucocorticoids on the provi­
ral genome has been demonstrated (56).
The mechanism of reactivation is still controversial. For example, reactivation of
murine cytomegalovirus is induced by several stimuli; most of them are known to
be immunosuppressive. Nevertheless, non-immunological effects accompany these
treatments and could represent the true reactivation stimulus (21). Cyclophospha­
mide is a potent immunosuppressive drug. It induces reactivation of several herpes­
viruses: HSV (20) and Pigeon herpesvirus 1 (65), but has no effect on BHV-1
latency (42). The dose of cyclophosphamide used also provokes alterations of DNA
(6). Therefore, it cannot be concluded that cyclophosphamide effect is due to
immunosuppression. Finally, as the genes involved in latency are being identified,
the study of the regulation of their expression will certainly contribute to the know­
ledge of the reactivation phenomenon.
RE-EXCRETION
Re-excretion is effective only when reactivated viruses pass through several bar­
riers. In the case of nervous latency (trigeminal ganglion), viruses migrate through
the sensitive branches of trigeminal nerve and finally reach skin or respiratory
mucosa. At this stage, virus multiplication can be stopped by cell-mediated cyto­
toxicity (52). Non-specific immune mechanisms are also involved: monocytesmacrophages, NK cells and interferon also restrict virus multiplication (28). Humo­
ral immunity plays a limited role since herpesviruses pass from cell to cell through
intercellular bridges (8). Afterwards, when virus is released in extracellular space,
neutralization acts in limiting the re-excretion of infectious virus.
Virus re-excretion is therefore a phenomenon controlled by specific immunity.
This is the reason why re-excretion is not always observed after reactivation,
although it is a direct consequence of reactivation. Four cases can be considered:
(1) No re-excretion occurs, but viral multiplication is able to boost the immune
response and specific immunity may still be stimulated (61);
(2) the specific immunity may no longer be stimulated, reactivation is induced,
but it can be demonstrated neither by a booster response nor by an episode of reexcretion;
— 814 —
(3) re-excretion is not accompanied by a booster immune response: reactivation
has been provoked in highly immunized animals; some of the reactivated viruses
escape the immune defence and are excreted. In this case, the period of re-excretion
is short and virus is re-excreted at very low titres (41);
(4) re-excretion is produced and is accompanied by a booster immune response
(41).
EPIZOOTIOLOGICAL SIGNIFICANCE OF L A T E N C Y
The epizootiological significance of latency is obviously the persistence of the
virus in the population by silent carriers, without evidence of clinical disease. These
silent carriers seem healthy and, in certain cases, cannot be detected by the usual
serological tests (1).
Prophylactic measures based upon vaccination have been widely used to prevent
the clinical manifestations of herpesvirus infections in domestic animals, but they
are unable to prevent the installation of a strain in a latent state or to eliminate a
latent virus carried at the time of vaccination. Moreover, in such animals, vaccina­
tion does not totally prevent the re-excretion of latent virus and the subsequent dis­
semination of wild-type virus to the surrounding animals. Attenuated live vaccines
offer the animal the most complete range of immunogenic components necessary
for a well-balanced immune response (53), but attenuated vaccine strains may per­
fectly well remain in a latent state (43). Cattle vaccinated by an attenuated strain of
BHV-1 and subsequently challenged with a virulent strain re-excrete both viruses
after reactivation (35). The presence of one virus in a latent state does not exclude
latency of another virus: coinfection with two strains is the best procedure to estab­
lish latency of two viruses, if the virulence of both strains is the same; superinfection
is less efficient, because multiplication of superinfecting virus may be severely res­
tricted by the immune response (62; Yierrel D. L., Blyth W. A. and Hill T. J., per­
sonal communication). As recombination occurs easily for HSV and SHV-1, for
example, appearance of virulent recombinants must be considered in animals
latently infected by two vaccine strains. A recent work has shown that virulent
recombinants have been obtained by in vitro recombination between attenuated
strains of SHV-1 (Lomniczi B., Kaplan A.S. and Ben-Porat T., personal communi­
cation).
Newly developed attenuated vaccines must therefore have the following charac­
teristics:
(1) They must be able to prevent re-excretion, since vaccination does not impede
the installation of a virulent strain in a latent form;
(2) they have to be deleted in genomic regions involved in latency to prevent
their own latency;
(3) they must be deleted in virulence genes and these deletions must be situated
in different parts of the genome to prevent the appearance of virulent recombi­
nants;
(4) they must possess markers easily identifiable: biological or biochemical mar­
kers, but particularly antigenic markers. This point will be discussed below.
Successful programmes of eradication of herpesvirus infections will take into
account the phenomenon of latency. Silent carriers do not show any clinical sign of
— 815 —
t h e i n f e c t i o n a n d s e r o l o g i c a l a n a l y s i s fails t o i d e n t i f y a l l t h e s e l a t e n t l y i n f e c t e d a n i ­
m a l s . M o r e o v e r , v a c c i n a t i o n l e a d s t o e p i d e m i o l o g i c a l c o n f u s i o n , s i n c e it is u s u a l l y
impossible t o distinguish b y serological testing between animals vaccinated a n d
those infected b y a virulent strain. Isolated viruses c a n sometimes b e identified b y
biological m a r k e r s (e.g. thermosensitive vaccine strain) or b y biochemical m a r k e r s
(e.g. restriction e n d o n u c l e a s e fingerprinting). F u r t h e r research s h o u l d b e d e v o t e d t o
the development of vaccine strains which h a r b o u r original antigenic properties,
with respect t o t h e p a r e n t a l strain, w h i c h d o n o t affect their i m m u n o g e n i c i t y (Kit
S., S h e p p a r d M . a n d K i t M . , p e r s o n a l c o m m u n i c a t i o n ) . T h e r e c e n t d e v e l o p m e n t o f
TK-negative vaccine viruses introduces n o t only a new a t t e n u a t e d p r o p e r t y , b u t also
a strain m a r k e r (TK-negative) (22, 2 3 , 31). T h e d e v e l o p m e n t of diagnostic m e t h o d s
a b l e t o d e t e c t a l l t h e l a t e n t c a r r i e r s a n d , selectively, t h e v a c c i n a t e d a n i m a l s will b e
of great help f o r e r a d i c a t i o n p r o g r a m m e s .
CONCLUSIONS
Latency increases t h e complexity of t h e epizootiology of herpesvirus infections.
T h e c o n s e q u e n c e s o f latency a r e difficult t o describe b e c a u s e o f t h e a c c u m u l a t i o n
of d a t a . T h e r e is a n e e d t o p o s s e s s a c o n c e p t u a l a p p r o a c h t o t h e i n t e r a c t i o n s b e t ­
ween t h e a n i m a l a n d t h e latent virus. It w o u l d , therefore, b e useful t o h a v e a m o d e l
which could analyse a n y epizootiological situation a n d suggest a n evolution o f t h e
system. I n this context, logical analysis w o u l d b e of great h e l p (46).
Molecular biology h a s provided n e w tools for t h e study of herpesvirus latency
a n d pathogenesis: in t h e near future, t h e knowledge of t h e genetic control of
l a t e n c y a n d v i r u l e n c e will l e a d t o t h e p r o d u c t i o n o f s a f e v a c c i n e s a t t e n u a t e d b y s p e ­
cific d e l e t i o n s i n t h e g e n o m e . T h i s is a f u r t h e r s t e p t o a n e w r a t i o n a l p r o p h y l a x i s
w h i c h s h o u l d fully p r e v e n t t h e e s t a b l i s h m e n t o f l a t e n t v i r u s a n d t h e r e - e x c r e t i o n o f
latently carried virus.
*
**
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