viruses-mechanisms of immune evasion and involvement in periodontal diseases

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R. Periodontia - Junho 2009 - Volume 19 - Nmero 02

INTRODUCTION

Periodontitis is a disease attributable to multiple

infectious agents and interconnects cellular and

humoral host immune responses. However, it has

been difficult to unravel the precise role of various

putative pathogens and host responses in the

pathogenesis of periodontitis. Some uncertainties

about the differences in loss of periodontal

attachment and alveolar bone or limited gingival

inflammation with comparable levels of risk factors

have galvanized efforts to find additional etiologic

factors for periodontitis (SLOTS, 2005). Recently, it was

suggested that certain viruses might also influence

the development and severity of periodontal diseases,

though the cause of gingivitis and periodontitis is

credited to bacteria colonizing tooth surfaces and

initiating the major mechanisms of periodontal

destruction (CAPPUYNS et al, 2005). Its obvious that

others factors beyond biofilm are important in the

pathogenesis of periodontitis, like tobacco smoking

and genetically determined variations in inflammatoryresponse patterns. But viruses can also interfere on

immune responses though immune modulators

encoded within viral genomes, which include proteins

that regulate antigen presentation, function as

cytokines or cytokine antagonists, inhibit apoptosis,

VIRUSES: MECHANISMS OF IMMUNE EVASION AND

INVOLVEMENT IN PERIODONTAL DISEASES A REVIEW

ARTICLE

Vrus: mecanismos de evaso imunolgica e envolvimento nas doenas periodontais - Um artigode reviso

Giselle Segnini Senra1, Adriana Aigotti Haberbeck Brando2, Warley David Kerbauy3

RESUMO

Periodontite uma doena multifatorial com diversos

padres clnicos no precisamente explicados pelo papel

etiolgico de bactrias. Herpesvrus tm sido encontrados

em locais afetados por periodontite, pela PCR. Sabe-se que

os herpesvrus afetam a regulao imune; assim, variaes

nas respostas inflamatria e imune atribudas a eles po-

dem reduzir a resistncia do hospedeiro contra coloniza-

o subgengival e multiplicao de patgenos periodontais.

Mais investigaes experimentais para avaliar a real relao

dos efeitos observados em estudos descritivos podem tra-

zer provas causativas e conclusivas dos efeitos especficos

dos herpesvrus nas doenas periodontais.

UNITERMOS:

1Doutoranda em Biopatologia Bucal (FOSJC Unesp)

2Professora Doutora da Disci plina de Patologia Geral (FOSJC Unesp)

3Professor Doutor da Disciplina de Periodontia (FOSJC Unesp)

Recebimento: 11/02/08 - Correo: 28/07/08 - Aceite: 29/01/09

H e r p e s v i r i d a e / i m u n o l o g i a ;

Citomegalovirus; Herpesvirus 4 Humano; Simplexvirus;

Periodontite/etiologia. R Periodontia 2009; 19:38-44.


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R. Periodontia - 19(2):38-44

39

and interrupt the complement cascade (SPRIGGS, 1996).

Thus, a situation of viral-bacterial interaction could occur in

the oral cavity without a denial of the argument for a major

etiological role of bacteria in human periodontal disease.

The purpose of this review is giving an overview of theviruses and its mechanisms of immune evasion and

pathogenesis, highlighting specifically those viruses that may

be potentially involved in periodontal diseases, in the absence

of HIV viruses and AIDS.

MATHERIAL AND METHODS

A sear ch was pe r fo rmed on Medl ine (ht tp ://

ncbi.nlm.nih.gov/PubMed/medline.html) using the search

terms viruses periodontal and Limits: Publication Date from2006/07, Humans. This search resulted in 35 articles and all

related to AIDS were excluded. Another search was

performed on these articles references, including all that bring

relevant information about the theme.

Mammalian viruses

Viruses occupy a unique position in biology. They are

restricted intracellular agents, which are metabolically and

pathogenically inert outside the host cell (SLOTS, 2005),

depending on living cells for replication.

Individual virus families have targeted many common

immunological principles. Viruses that belong to different

families are subject to different constraints. The genome size

of RNA viruses is limited and they have the advantage of

being able to use mutation to escape immune control while

the genome size of DNA viruses allows a larger number of

genes to be devoted to host control (ALCAMI &

KOSZINOWSKI, 2000).

Viruses can exist in two forms: extracellular virion particles

and intracellular genomes. Virions are more resistant to

physical stress than genomes but are susceptible to humoral

immune control. Virus genomes can be maintained in host

cells by limited gene expression and can evade the host

immune response. Nevertheless, viruses replication and

transfer to a new host are essential for them, so they have

evolved strategies to evade immune control mechanisms like

wi th the immunoregu lator y prote in s wi th homo lo g

sequencing cellular genes. These stolen genes from the host

modify the viruses for their benefit and the viral homology ofhost genes involved in the immune system are mainly found

in large viruses, like the herpesviridae (ALCAMI &

KOSZINOWSKI, 2000), a virus family of DNA, doubled-

stranded, enveloped viruses. DNA viruses replicate in the

nucleus and are more likely to persist in the host. Enveloped

viruses typically initiate cell-mediate inflammatory responses

and delayed type hypersensitivity, which affect viral replication

by killing mammalian cells that express viral proteins. Disease

is often due to inappropriate immune responses and this

explains why herpesvirus reactivation is triggered by a numberof immunosuppressing factors. Naked viruses are controlled

mainly by antibody, and vaccines are generally effective

(SLOTS, 2005). Because of the lack of effective therapeutics

and vaccines, herpesvirus diseases continue to constitute a

significant problem for public health (SLOTS, 2005). Recent

studies have revealed an association between some of the

members of herpesvirus family and destructive human

periodontal disease.

Herpesviruses and mechanisms of immune evasionOf the approximately 120 identified different

herpesviruses, eight major types are known to infect humans

(table 1), namely, herpes simplex virus (HSV) type 1 and 2,

varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human

cytomegalovirus (HCMV), human herpesvirus HHV-6, HHV-

7, and HHV-8 (Kaposis sarcoma virus). Humans are the only

source of infection for these eight herpesviruses. Human

herpesviruses are classified into three groups (,,) based

upon details of tissue tropism, pathogenicity, and behavior

under conditions of culture in the laboratory (SLOTS, 2005).

Herperviruses can occur in a latent or in a productive

(lytic) state of replication. During the latent phase the viral

genome integrates within the host cells genome. They may

undergo reactivation and re-enter the productive phase as

consequence of declining herpesvirus-specific cellular

immunity. The genomic transcription may induce changes in

host cell expression of genes that encode proteins involved

in immunity and host defense (SLOTS, 2005).

The innate host response consists of a complex system

of mechanical and secreted defenses, immediate chemokine

and interferon responses, and rapidly recruited cellular

defenses. Cellular lymphocyte response attempts to eliminate

virus-infected cells. It is essential to limit initial viral replication

and to facilitate appropriate adaptive immune response.

Cytotoxic T- lymphocyte (CTL) and NK cells are the most

important effectors in the maintenance of latency. T-cell

response to herpesvirus changes from a predominantly CD4+

response early in infection to a CD8+ response during latent

infection (SLOTS, 2005).The mechanisms that viruses use to perpetuate

themselves within the host is reflected in the varied immune

modulators encoded in viral genomes which include selective

regulation of host antigen presentation, production of growth

factors that function on host cells, and antagonism of


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immune function through the use of soluble versions of

cytokine receptors. In many cases, these viral proteins

function to assist the virus in avoiding host immune

surveillance, while in other instances they clearly function to

protect the host from the sometimes deleterious effects ofthe virus-induced inflammatory response. Not surprisingly,

herpesviruses are considered masters of host immune

evasion, employing a variety of strategies that ultimately allow

the establishment of latent infections and occasional

reactivations that ensure efficient perpetuation of the virus

within a population (SPRIGGS, 1996).

Cytokines are potent, soluble proteins that play key ro-

les in the induction and maintenance of inflammation,

immune response, differentiation, and embryonal

development (SPRIGGS, 1996). Th1 proinflammatory immuneresponses aim to clear the host of intracellular pathogens.

Th1 cytokines favor the development of a strong cellular

immune response whereas Th2 cytokines favor a strong

humoral immune response. IL-10, a Th2 cytokine,

antagonizes Th1 proinflammatory responses (SLOTS, 2005).

Herpesviruses modulate the activity of chemoattractant

cytokines that regulate leukocyte trafficking to sites of

infection, preventing Th1 anti-viral responses. HCMV and

EBV express IL-10 homologs downregulating the production

of IL-12 and also inhibiting the production of TNF, IL-1 and

other cytokines in macrophages. IL-12 is required for the

production of IFN which induces an anti-viral state in the cell

limiting virus replication (SLOTS, 2005; SPRIGGS, 1996;

ALCAMI & KOSZINOWSKI, 2000). Viruses also display great

inventiveness when it comes to diverting potent antiviral

cytokine and chemokine responses to their benefit.

Prostaglandin E2

(PGE2), which is a major mediator of

periodontal inflammatory response, increases rapidly in

response to exposure of cells to herpesviruses and to bacterial

lipopolysaccharide; however, PGE2

may under certain

circumstances serve to support HCMV replication (SLOTS,

2005). Some cytokine homologs might also increase

proliferation of cells that are targets for viral replication

(ALCAMI & KOSZINOWSKI, 2000). One interesting

mechanism is the mimicry of cytokines (virokines) and

cytokine receptors (viroceptors) by large DNA viruses like

herpesviruses.

The complement system is a major non-specific host

defense mechanism. Viruses protect the membranes ofinfected cells and the lipid envelopes of virus particles from

complement lysis by encoding homologs inhibitors of the

membrane-attack complex. HCMV borrows host cellular

factors (CD59), which normally protects cells from

complement lysis, and incorporating them into the viral en-

velope (ALCAMI & KOSZINOWSKI, 2000).

Apoptosis can be triggered by a variety of inducers,

including infectious agents such as viruses. Apoptosis can

be considered an innate cellular response to limit viral

propagation, and viruses express proteins that block death

response; however, apoptosis might also facilitate virus

dissemination, and viral pro-apoptotic mechanisms have also

been described (ALCAMI & KOSZINOWSKI, 2000). Expression

of the EBV latent proteins protects latently infected B cells

from apoptosis but cannot inhibit apoptosis of naive B

lymphocytes as a result of primary EBV infection (SPRIGGS,

1996).

The major histocompatibility complex (MHC) class I

molecules are expressed on the surface of virtually all somatic

cells. CTL recognition of the viral antigen in the context of

the self MHC molecules leads to cellular activation, resulting

in both lysis of the infected cell and production of cytokines

and other factors that allow the expansion of the virus-specific

CTL population. HSV provides an example of interference

with virus-specific CTL recognition through regulation of

MHC class I/ peptide complex expression. HSV-1 and HSV-2,

like all herpesviruses, shut off MHC class I expression late

in infection as a result of overall diminished host

protein synthesis. HCMV can exhibit a structure with

significant homology to MHC class I playing a role in

interfering with normal MHC class I transport and function

(SPRIGGS, 1996).

Increased attention has focused on the possible clinicalsignificance of HCMV-induced immunosuppression in

immunocompetent individuals. HCMV seroposivity is

associated with higher degrees of CD8+ clonality in the

immunocompetent elderly, which may be associated with

aging (BOECKH & NICHOLS, 2003).

Herpesviruses Abbreviation Herpes

groupHerpes simplex virus type 1 HSV-1

Herpes simplex virus type 2 HSV-2

Varicella-zoster virus VZV

Epstein-Barr virus EBV

Human cytomegalovirus HCMV

Human herpesvirus 6 HHV-6



Table 1

HERPESVIRUSES THAT INFECT HUMANS

(ADAPTED FROM SLOTS, 2005)


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Pathogenesis of herpesvirus in periodontal disease

The pathogenic process of periodontitis includes dynamic

interactions among various infectious agents and

interconnects cellular and humoral host responses. However,

despite a long history of research into the pathobiology of

periodontitis, a definitive statement about its probable cau-

ses on a molecular level remains elusive. Bacterial pathogens

are necessary antecedents for the development of

periodontitis but the mere amount of biofilm does not seem

to provide sufficient basis for explaining important

clinicopathologic features of the disease. Bacterial infection

alone may not explain the conversion of gingivitis to

periodontitis (SLOTS et al,2002), rapid tissue destruction

around teeth exhibiting little plaque, the propensity of

periodontitis to proceed with periods of exacerbation and

remission, and the tendency of periodontal tissue breakdown

to advance in a localized and bilaterally symmetrical pattern

(KUBAR et al, 2005). Recent studies (some examples in table

2) suggest that periodontal hespesviruses comprise an

important source for triggering periodontal tissue destruction(SAYGUN et al, 2004) and the identification of a herpesvirus

factor in the development of periodontitis may help clarify

hitherto unexplained clinical and pathophysiologic

characteristics of the disease (KUBAR et al, 2005).

The involvement of herpesviruses in the etiology of

periodontal diseases is suggested by: 1) higher frequency of

virus detection in gingival tissue and subgingival plaque of

periodontitis sites than in healthy sites; 2) higher frequency

of virus detection in gingival crevicular fluid (GCF) from

periodontal disease sites than from gingivitis/healthy sites;

3) detection of activated herpesvirus in the GCF of periodontal

lesions; 4) interaction of herpesviruses with periodontal

pathogens (CAPPUYNS et al, 2005).

A herpesvirus-bacterial pathogen model has been

proposed in which viral infection may exert periodontopathic

potential. Herpesviruses can infect or alter structural cells and

host defense cells of the periodontium and thereby reduce

host resistance against subgingival colonization and

multiplication of periodontal pathogens (CONTRERAS et al,

2000; CASSAI et al, 2003) or exert direct cytopathic effects

on fibroblasts, keratinocytes, endothelial cells, inflammatory

cells, such as PMN leukocytes, lymphocytes and

macrophages, and possibly on bone cells (SLOTS &

CONTRERAS, 2000). Several studies examined a possible

association between potential periodontopathic bacteria andherpesviruses in subgingival plaque (KAMMA et al, 2001;

SLOTS etal, 2002; KAMMA & SLOTS, 2003; SLOTS et al, 2003;

SAYGUN et al, 2004).

HCMV genomic sequences, detected by PCR, occur with

elevated frequency in severe adult periodontitis, localized and

Table 2

HERPESVIRUSES DETECTED IN HUMAN PERIODONTAL SITES BY PCR

Author Sites Herpesvirus (rates %)

CONTRERAS et al, 2000 Periodontal pocket (paper points) HSV (21*e 0**); HCMV (64*e 9**);

EBV-1 (43*e 18**); EBV-2 (21*e 0**);HHV-6 (not found); HHV-7 (7*e 0**);HHV-8 (not found)

Gingival tissue HSV (57*e 9**); HCMV (86*e 18**);EBV-1 (79*e 27**); EBV-2 (50*e 0**);HHV-6 (21*e 0**); HHV-7 (43* e 0**);HHV-8 (29* e 0**)

CONTRERAS & SLOTS, 2001 Periodontal pocket**,B , , HSV-1(100); HSV-2 (not found)(paper points)

CASSAI et al, 2003 Gingival tissue HHV-6 (8B ;0**e 10***);HHV-7 (77B ;54**e 70***);

HHV-8 (7.7B

;7.7**e 0***)KUBAR et al, 2004 Periodontal pocket (curette) HCMV (68.8 e 0***)

KUBAR et al, 2005 Periodontal pocket+,gingival tissue++ HCMV (78+ e 33++);HCMVB (46+ e 9++);EBV (89+ e 78++);EBVB (46+ e 46++)

SAYGUN et al, 2005 Periodontal pocket (curette), EBV B , ; HCMVB ,

gingival tissue and saliva

KONSTANTINIDIS et al, 2005 Periodontal pocket (paper points) EBV (50B e 23***)

(Periodontal status at sample sites: periodontitis*, healthy sites**, periodontally healthy subjects***, chronic periodontitisB , aggressive periodontitis, HIV-associated periodontitis.)


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generalized aggressive periodontitis, PapillonLefvre

syndrome periodontitis, acute necrotizing ulcerative gingivitis,

periodontal abscesses, and it is also closely associated with

symptomatic periapical diseases (SLOTS et al, 2004).

Herpesviruses establish lifelong persistent infections. HCMVinfection involves an asymptomatic latent phase interrupted

by periods of recrudescence where viral replication and

possibly clinical disease become manifest. HCMV reactivation

is triggered by a number of immunosuppressive factors, some

of which have been shown also to be risk factors/indicators

of periodontitis. Stressful events induce the release of

corticosteroids, which have the potential to activate HCMV.

Tobacco products may interact with and

reactivate periodontal herpesviruses and may decrease

herpesvirus infectivity titers, which may partly explain theincreased risk for periodontitis from tobacco usage. The ability

of HCMV and other herpesviruses to cause latent infections

that periodically reactivate has some similarity with the

relapsing-remitting course of periodontitis (SLOTS, 2004).

Active herpesvirus infections are potentially more deleterious

than latent herpesviruses, thus both differences in periodontal

distribution and rate of activation among herpesvirus-positive

sites may contribute to the site-specific nature of periodontal

disease progression (SLOTS & CONTRERAS, 2000).

In nonoral diseases, it is known that HCMV infection

can increase the incidence of bacterial and fungal infections,

aggravate the severity of concurrent microbial infections, and

accelerate the tempo of infectious disease progression.

Although less studied, EBV and bacterial pathogens may also

act synergistically in nonoral infectious diseases. A similar

theory for periodontitis focuses on the potential of

periodontal HCMV/EBV to subvert local host defenses,

thereby enhancing the aggressiveness of subgingival bacteria

(KUBAR et al, 2005).

The effectiveness of host immune response in dealing

with periodontal pathogens is a major determinant of clinical

periodontal disease. Impaired immune responses in

periodontal sites may take place due to local hypoxia

decreasing host cell activity, diabetes mellitus, genetic

immune deficiencies, and various viral and bacterial infections.

Actually, increased attention has focused on the possible

significance of HCMV-induced immunosuppression in

immunocompetent individuals (BOECKH & NICHOLS, 2003).

Herpesvirus infections can cause both cytopathogenicand immunopathogenetic eects, and although the relative

contribution of the two pathogenic mechanisms to

destructive periodontal disease is not known, it is likely that

the early stages of periodontitis in immunologically naive

hosts mainly comprise cytopathogenic events, whereas most

clinical manifestations in immunocompetent individuals are

secondary to cellular or humoral immune responses (KUBAR

et al, 2005).

Bacterial components such as lipopolysaccharide can

potently activate production of interleukin-1 and other boneresorptive mediators at inflamed sites, causing connective

tissue destruction and alveolar bone loss. Periodontal infection

may also induce host cells to elaborate increased levels of IL-

1, TNF, PGE2

and other tissue-destructive products.

However, it has proved difficult to elucidate host responses

that are associated with periodontal disease stability or

progression (SLOTS et al, 2002). Even if proinflammatory

activities basically serve a positive biological goal by aiming to

overcome infection or tissue invasion by infectious agents,

they can also give rise to detrimental effects when a challengebecomes overwhelming or with a chronic pathophysiological

stimulus (SLOTS et al, 2004).

Bacterial infection and other conditions that promote

diapedesis of inflammatory cells into tissue would increase

the possibility of initiating a local HCMV infection (CONTRERAS

et al, 1999). Reactivation of HCMV commonly occurs in

patients with bacterial sepsis (BOECKH & NICHOLS, 2003).

Recent studies have shown that reactivation of HCMV in

periodontitis lesions may be related to progressing periodontal

disease due to the upregulation gene IL-1 and TNF

expression in monocytes and macrophages by active HCMV

infection at the periodontitis site (CONTRERAS et al, 2000;

WARA-ASWAPATI & AURON, 2003. These cytokines are

positively associated with the severity of destructive

periodontal disease and may subsequently upregulate matrix

metalloproteinases activity, which may mediate destruction

of the extracellular matrix of gingiva, periodontal ligament and

alveolar bone and also down-regulate tissue inhibitors of

metalloproteinases (CONTRERAS et al, 1999).

In tissues with periodontitis a high proportion of

inflammatory cells are infected by herpesvirus. Neutrophils,

monocytes/macrophages, T and B-lymphocytes were isolated

from gingival biopsies of periodontitis lesions. HCMV

and HSV mainly infect periodontal monocytes/macrophages

and T-lymphocytes while EBV-1 infects periodontal B

lymphocytes (CONTRERAS et al, 1999). PMN leukocytes have

consistently been found to carry greatest viral burden

compared with monocytes but they do not carry latent

HCMV, whereas monocytes are a true site of virus latency(GERNA et al, 2004).

HCMV infection may induce abnormalities in adherence,

chemotactic, phagocytic, oxidative, secretory, and bactericidal

activities of neutrophils. Phagocytic and bactericidal capacities

of periodontal neutrophils seem to be significantly impaired


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in subjects carrying herpesviruses in oral lymphocytes and

epithelial cells, as compared to virus-free persons. The

functional defects of neutrophils identied in localized

aggressive periodontitis patients may in part be due to a

concurrent HCMV active infection in these patients (SLOTS,2004). Thus, oxidative respiratory burst of macrophages and

its ability to perform effective phagocytosis is also impaired

by HCMV (GERNA et al, 2004). The ability to inhibit the

expression of macrophage surface receptors for LPS also

impairs responsiveness to Gram negative infections (SLOTS

et al, 2004).

Endothelial cell injury caused by HCMV could allow

invasion across mucosal barriers in both the lung and

gastrointestinal tract (BOECKH & NICHOLS, 2003) and this

mechanism may explain the association between HCMV andacute necrotizing ulcerative gingivitis. The initial trigger of

HCMV-induced pathology is represented by the bidirectional

interaction between circulating leukocytes and endothelial

cells (GERNA et al, 2004).

HCMV and EBV-1 may interfere with healing in

regenerative periodontal therapy, perhaps because of

cytokines release or infection of periodontal fibroblasts (SLOTS

& CONTRERAS, 2000). KUBAR et al related elevated

occurrence of HCMV and EBV DNA copies in aggressive

periodontitis lesions relative to chronic periodontitis lesions,

and the increase in herpesvirus counts with increasing severity

of periodontitis, providing substantial support to a

periodontopathic role of the two viruses which are also found

in periodontal abscesses (SAYGUN et al, 2004)

EBV-1, the second most prevalent virus detected in biopsy

specimens, is a potent B-lymphocyte activator, a cell

associated with periodontal disease progression. These

viruses encode a protein with structural and functional

similarity with IL-10 and polarize the immune system toward

a Th2 response that seems to be related to progressive

periodontal disease, whereas a Th1 response has been

associated with protection against periodontitis (CONTRERAS

et al, 1999).

EBV-2, HHV-6 and HSV seem to exhibit little or no

association with most types of destructive periodontal disease.

No information is available on the periodontal occurrence of

HHV-7 and HHV-8 (CONTRERAS et al, 2000). HHV-6 has been

postulated as a modifier of HCMV replication, given evidence

that it stimulates secretion of TNF (BOECKH & NICHOLS,2003). The significance of HHV-7 DNA in periodontal lesions

needs to be determined. The mere presence of viral DNA does

not necessarily implicate an etiologic role, either as a direct or

as a coinfective agent. PCR analysis does not discriminate

among latent, persistent and productive infections. It is

important to determine precisely the state of viral replication,

since it has been suggested that herpesvirus pathogenesis

might be associated with not only massive lytic infection but

also with low levels of replication (CASSAI et al, 2003).

Therefore, it is assumed that the ability of herpesvirusesto express cytopathogenic effects, immune evasion,

immunopathogenicity, latency, reactivation from latency, and

tissue tropism is of relevance for the development of

periodontitis (SLOTS, 2005), and they may not act as simple

by-standers in periodontal disease (CONTRERAS et al, 2000).

SLOTS & CONTRERAS (2000). The hypotheses is that the

pathogenesis of some types of periodontitis is a multistep

process, involving a complex interaction between

herpesviruses, a range of bacterial and host factors, and a

variety of disease-modulating environmental factors. Thishypothesis is challenged by several arguments regarding

sampling, methods and interpretation (CAPPUYNS et al,

2005). Regardless the strong association between some

herpesviruses and periodontitis, the exact role of these viruses

in the pathogenesis of periodontitis remains to be established.

Most studies were observational, when only a statistical

association was seen. These data are intriguing, but

conclusive proof for a specific effect requires more trials to

evaluate whether the effects seen in observational studies

are truly related and if such associations are causative.

The identification of virus-encoded proteins that interact

with the host immune system is a rapidly expanding area of

viral immunology. The elucidation of the function of these

virus molecules will assist the understanding of viral

pathogenesis and provide tools to study and manipulate the

normal host immune response (SPRIGGS, 1996).

ABSTRACT

Periodontitis is a multilayered factors disease with diverse

clinical features not precisely explained by the etiologic role

of bacteria. Herpesviruses have been found in periodontally

affected sites by PCR. Herpesviruses are known to exert

immune regulation and thus, variations on inflammatory and

immune responses attributed to them may reduce host

resistance against subgingival colonization and multiplication

of periodontal pathogens. More trials to evaluate whether

the effects seen in observational studies are truly related to

herpesviruses could bring a causative and conclusive prooffor their specific effect in periodontal disease.

UNITERMS: H e r p e s v i r i d a e / i m m u n o l o g y ;

Cytomegalovirus; Herpesvirus 4, Human; Simplexvirus;

Periodontitis/etiology.


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