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Brogden KA, Guthmiller JM, editors. Polymicrobial Diseases. Washington (DC): ASM Press; 2002.

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Chapter 16Interactions between Herpesviruses and Bacteria in Human Periodontal Disease


School of Dentistry, MC 0641, University of Southern California, Los Angeles, CA 90089-0641.

Destructive periodontal diseases are infectious disorders, but the specific mechanisms by which tooth-supportive tissue is lost remain obscure. This chapter proposes an infectious disease model for severe periodontitis in which herpesviral-bacterial interactions assume a major etiopathogenic role. Herpesviruses, especially cytomegalovirus (HCMV), Epstein-Barr virus type 1 (EBV-1), and HCMV/EBV-1 dual infection, have recently been identified in most of the advanced periodontitis lesions of children, adolescents, and adults. Herpes simplex virus (HSV) type 1, human herpesvirus 6 (HHV-6), HHV-7, and HHV-8 (individuals infected with the human immunodeficiency virus [HIV]) can also be detected in some periodontitis lesions. Evidence suggests that herpesvirus-infected periodontitis lesions harbor elevated levels of periodontopathic bacteria, including Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Dialister pneumosintes, Prevotella intermedia, Prevotella nigrescens, and Treponema denticola. Conceivably, periodontal active herpesvirus infection impairs periodontal defenses, thereby permitting subgingival overgrowth of periodontopathic bacteria. It is further hypothesized that gingival tissue plays a role in the maintenance of herpesvirus load in vivo and that the shedding of herpesviruses from periodontal sites during reactivation plays a role in virus transmission. Understanding the significance of herpesviruses in human periodontitis may allow for improved diagnosis and, ultimately, disease prevention.

Periodontal Disease

The term periodontal disease represents a variety of clinical manifestations of infectious disorders affecting the tooth-supporting tissues. Traditionally, periodontal disease is divided into gingivitis and periodontitis. Gingivitis indicates an inflammatory disease that is limited to gingiva with no clinical evidence of loss of periodontal ligament fibers or alveolar bone. Gingivitis sites show pocket depths typically ranging from 2 to 4 mm. The disease is reversible after instituting proper oral hygiene.

Periodontitis denotes an inflammatory destruction of the periodontal ligament and supporting bone. The course of periodontitis is characterized by intermittent exacerbations of the disease. Some periodontitis patients remain stable for many years, while other patients have a history of sporadic or gradually advancing disease that eventually may lead to tooth mobility and tooth loss. Although periodontitis has been found to be reversible, its reversibility is difficult to achieve and limited in degree, often requiring surgical regenerative procedures that may carry high financial costs.

Periodontitis is the major cause of tooth mortality in many developed countries, and most developing nations (59). Periodontitis, as measured by the presence of periodontal pockets exceeding 4-mm depth on an average of three to four teeth, affects approximately 30% of the U.S. population (58). Periodontal pockets of depths of 7 mm or more are present in less than 5% of the U.S. adult population (58) and in 2 to 28% of adults in Western European countries (90).

Periodontitis can be classified by type of patient (child, adolescent, adult, compromised host), by etiology (bacterial, fungal, or viral infection), by rate of progression (stable, aggressive), by extent of affected dentition (localized, generalized), by size of lesions (initial, moderate, or advanced breakdown), by morphology of lesions (angular or horizontal defect), by type of associated gingivitis (chronic, necrotizing), and by effectiveness of treatment (responsive, recalcitrant). Classification of periodontitis based on specific infectious agent etiology would facilitate treatment decisions, but such a classification system is presently unavailable.

Periodontal Infections

Since the mid-1970s, significant inroads have been made into the microbiology and immunology of periodontal diseases. We can now feel confident that periodontitis represents several infectious disease entities with different pathogenic mechanisms (78).

The significance of bacteria in the development of virtually all types of periodontal disease is undisputable. While it is clear that approximately 500 bacterial species can be identified in periodontal pockets (64), it is also clear that relatively few species are considered legitimate pathogens of periodontitis. The bacterial mass is critical for the development of gingivitis and some types of chronic periodontitis ("nonspecific" infection), while the type of bacteria seems to be of greater importance in the initiation of aggressive periodontitis ("specific" infection). Colonization of specific microbial pathogens together with microbial synergy, the host immune response, and various environmental risk factors are major determinants of the probability of acquiring destructive periodontal disease (78).

Important periodontopathic bacteria include gram-negative facultative (A. actinomycetemcomitans) and anaerobic rods (P. gingivalis, Bacteroides forsythus, D. pneumosintes) (76). Organisms of probable periodontopathic significance are P. intermedia, P. nigrescens, Campylobacter rectus, Peptostreptococcus micros, Fusobacterium species, Eubacterium species, β-hemolytic streptococci, Treponema species, and perhaps yeasts, staphylococci, enterococci, pseudomonads, and various enteric rods (76).

During the past 5 years, herpesviruses have emerged as putative pathogens in destructive periodontal disease (17, 62). In particular, HCMV and EBV-1 seem to play important roles in the etiopathogenesis of severe types of periodontitis. Genomes of the two herpesviruses are frequently detected in aggressive periodontitis of children, adolescents, and adults, in periodontitis of immunocompromised hosts, and in necrotizing types of gingivitis (77). Genomes of HSV type 1 (3, 18, 23) and HHV-6 and HHV-7 (14) have also been identified in periodontitis lesions. Kaposi's sarcoma-associated virus (HHV-8) has been detected in HIV-related periodontitis (49).

This chapter reviews the continually evolving field of herpesviral infections of the human periodontium and proposes a model for aggressive periodontitis that is based on a combined herpesviral-bacterial causation of the disease. Emphasis is placed on the possible role of HCMV and EBV in the development of human periodontitis.


For a general introduction to herpesviruses, the reader is referred to several authoritative reviews (2, 10, 40, 70). Herpesviral characteristics of potential importance in the pathogenesis of periodontitis are outlined below. Members of the herpesvirus family are composed of a double-stranded DNA genome contained within a nucleocapsid surrounded by a lipid envelope. To date, eight human viruses of the family Herpesviridae have been identified, namely, HSV types 1 and 2, varicella-zoster virus, EBV, HCMV, HHV-6, HHV-7, and HHV-8.

Most individuals become infected with herpesviruses early in life, and depending on the geographic location, between 60 and 100% of adults are carriers of HCMV and EBV (10, 40). A notable exception is HHV-8, which is contracted in adulthood. Primary herpesviral infections proceed with no signs of clinical disease in most individuals. The clinical manifestations of herpesvirus infections are very diverse and range in immunocompetent individuals from mild or subclinical disease to encephalitis, pneumonia, and other potentially lethal infections and to various types of cancer including lymphoma, sarcoma, and carcinoma (17). Herpesviral infections show a tendency to cell and tissue tropism, but the molecular basis for herpesviral tropism remains obscure.

HCMV infection is of great clinical significance in pregnant women, newborn infants with congenital infection, immunosuppressed transplant patients, and individuals with HIV infection (32). HCMV is the most common life-threatening infection in transplant and HIV-infected patients (32). HCMV has been also associated with cervical carcinoma and adenocarcinomas of the prostate and colon (22).

EBV is the causative agent of infectious mononucleosis and is implicated in the etiology of EBV-associated hemophagocytic syndrome, chronic active EBV infection lymphomas, inflammatory pseudotumor, lymphomatoid granulomatosis, Hodgkin's disease, nasopharyngeal carcinoma, and gastric carcinoma (46, 57). EBV was recently implicated in recurrent tonsillitis and tonsillar hypertrophy (24, 36). EBV is also associated with oral hairy leukoplakia and may show some relationship with rheumatoid arthritis and chronic fatigue syndrome.

Herpesviruses occur in a prolonged state of latency and in an active state. Latent viral genomes are almost entirely transcriptionally quiescent (71). Reactivating from latency results in renewed general viral gene expression (71). Herpesviruses are dependent on immune activating mechanisms for reactivation from viral latency to the production of a new viral progeny (82). Reactivation may occur spontaneously or as a result of concurrent infection, fever, drugs, tissue trauma, emotional stress, exposure to ultraviolet light, or other factors impairing the host immune defense.

Herpesviruses reside in and may functionally alter cells of central importance for regulating the immune system. HCMV infects most cell types and establishes latency in macrophage-granulocyte progenitors (41) and peripheral blood mononuclear cells (81). During symptomatic infection, HCMV DNA can be detected in polymorphonuclear leukocytes probably as a result of phagocytosis, although active viral replication may occasionally occur (53). EBV infects B lymphocytes, where it establishes latency (9), and may also infect monocytes (74) and polymorphonuclear leukocytes (43). Immunosuppression is the cardinal feature of herpesvirus-active infections.

Control of viral replication and prevention of pathology depend on both innate and adaptive immune mechanisms (66). Herpesvirus infections induce a strong antiviral immune response that nonetheless is incapable of eradicating the infection. The cellular immune response plays an important role in controlling resident herpesviral infections by means of major histocompatibility complex class I-restricted cytotoxic CD8+ T lymphocytes that recognize viral peptides on the surface of infected cells (71). Infants and children infected with HCMV/EBV dual infection may experience more severe disease and markedly stronger T-lymphocyte responses than children infected with HCMV or EBV alone (89). On the other hand, herpesviruses also encode several genes that interfere with the activation of major histocompatibility complex class I- and class II-restricted T lymphocytes and natural killer (NK) cells, modify the function of cytokines and their receptors, interact with complement factors, and modulate signal transduction and transcription factor activity as well as other cellular functions, thereby providing evasion strategies against antiviral specific immune responses (45).

Molecular testing is increasingly important in the diagnosis and monitoring of patients affected by viral diseases (4). PCR-based detection has revolutionized diagnostic virology by providing a sensitive and specific tool to detect and quantify viral DNA and RNA in clinical specimens (12). Use of PCR for detection of HCMV DNA can show HCMV in blood of almost all patients with overt HCMV disease, but low viral load can also be detected in a substantial number of patients with asymptomatic infections that never progress to disease. PCR techniques are also valuable in detecting chronic EBV infection in tissue and B lymphocytes, and are considerably faster and more sensitive than conventional tissue culture methods. Quantitative PCR may aid in differentiating a clinically significant herpesvirus burden from a latent one.

Herpesviruses in Periodontal Disease

The occurrence of HCMV and EBV-1 and selected periodontal pathogenic bacteria in disease-active and disease-inactive early-onset periodontitis lesions has been studied (38). In 16 patients, who each contributed samples from two progressing and two stable periodontitis sites of similar pocket depth, HCMV, EBV-1, and HCMV/EBV-1 coinfection were significantly associated with disease-active periodontitis (Table 1). Significant associations were also found between the presence of D. pneumosintes, P. gingivalis, and D. pneumosintes/P. gingivalis coinfection, and disease-active periodontitis (Table 1). Each periodontitis site that demonstrated HCMV/EBV-1 coinfection and all but one site showing D. pneumosintes/P. gingivalis coinfection revealed bleeding upon probing, a clinical sign of increased risk of progressive disease (42).

Table 1. Occurrence of HCMV and EBV-1 in 32 progressing and 32 stable periodontitis sites of 16 early-onset periodontitis patientsa.

Table 1

Occurrence of HCMV and EBV-1 in 32 progressing and 32 stable periodontitis sites of 16 early-onset periodontitis patientsa.

Localized juvenile periodontitis debuts at puberty, is confined to permanent incisors and first molars, affects mainly black individuals, and has a familial predisposition (44). Michalowics et al. (51) determined the occurrence of HCMV, EBV-1, P. gingivalis, and A. actinomycetemcomitans in subgingival plaque from 15 adolescents with localized juvenile periodontitis, 20 adolescents with incidental periodontal attachment loss, and 65 randomly selected healthy controls. All study subjects were Afro-Caribbeans living in Jamaica. The most parsimonious multivariate model for localized juvenile periodontitis included P. gingivalis (odds ratio, 8.7; 95% confidence limits, 1.7 and 44.2) and HCMV (odds ratio, 6.6; 95% confidence limits, 1.7 and 26.1). The odds of having localized juvenile periodontitis increased multiplicatively when both P. gingivalis and HCMV were present (odds ratio, 51.4; 95% confidence limits, 5.7 and 486.5), when compared with the odds associated with having neither of the two infectious agents. Apparently, P. gingivalis and HCMV are independently and strongly associated with localized juvenile periodontitis in Jamaican adolescents, and P. gingivalis and HCMV act synergistically to influence the risk for both the occurrence and the extent of disease. Electron microscopy studies have previously detected various types of virions in localized juvenile periodontitis lesions (11, 67).

Ting et al. (85) studied the relationship between HCMV activation and disease-active versus disease-stable periodontal sites in 11 localized juvenile periodontitis patients aged 10 to 23 years (Table 2). HCMV mRNA of the major capsid protein, indicative of viral activation, was detected in deep pockets of all five HCMV-positive patients with early disease (aged 10 to 14 years), but only in one of three HCMV-positive patients older than 14 years, and not in any shallow pocket tested. HCMV activation was found exclusively in periodontal sites having no visible radiographic crestal alveolar lamina dura, a sign of likely periodontal disease progression (68). HCMV activation has also been detected in severe periodontitis lesions of adults (16). Furthermore, periodontal sites with active HCMV infection were more heavily infected with A. actinomycetemcomitans than sites with latent HCMV infection. Ting et al. (85) hypothesized that during root formation of permanent incisors and first molars at 3 to 5 years of age, primary HCMV infection in tissues surrounding the tooth germ might alter the root surface structure and increase the susceptibility to future periodontal breakdown. HCMV infections in infants are able to cause marked changes in tooth morphology (83; M. Wacinska, J. Janicha, A. Remiszewski, and A. Wal, J. Dent. Res. 80:1294, abstr. 198, 2001), and teeth affected by localized juvenile periodontitis frequently show cemental hypoplasia (8). Subsequently, at the time of puberty, reactivation of periodontal HCMV or other herpesviruses due to hormonal changes may give rise to periodontal overgrowth of pathogenic bacteria and breakdown around teeth with damaged periodontium.

Table 2. Occurrence of HCMV and EBV-1 in deep and shallow periodontal sites of 11 localized juvenile periodontitis patientsa.

Table 2

Occurrence of HCMV and EBV-1 in deep and shallow periodontal sites of 11 localized juvenile periodontitis patientsa.

HCMV and EBV-1 have been detected in rare types of aggressive periodontitis in young individuals (Table 3). In a Hopi Indian population, a single adolescent showed generalized juvenile periodontitis and was the only study subject revealing periodontal HCMV/EBV-1 dual infection (F. B. Skrepcinski, S. Tetrev, T. E. Rams, B. Sutton, A. Contreras, and J. Slots, J. Dent. Res. 76:439, abstr. 3406, 1997). One periodontitis patient with Papillon-Lefèvre syndrome also presented periodontal HCMV/EBV-1 dual infection (88). One patient with Fanconi's anemia periodontitis demonstrated periodontal HCMV-active infection and HSV (56).

Table 3. Occurrence of HCMV and in rare types of aggressive periodontitis in young individuals.

Table 3

Occurrence of HCMV and in rare types of aggressive periodontitis in young individuals.

Acute necrotizing ulcerative gingivitis (ANUG) affects immunocompromised, malnourished, and psychosocially stressed young individuals and may occasionally spread considerably beyond the periodontium and give rise to a life-threatening infection termed noma/cancrum oris (55). Table 4 shows the distribution of herpesviruses in ANUG-affected and non-ANUG-affected children 3 to 14 years of age from Nigeria. A significantly higher prevalence of HCMV and other herpesviruses was detected in ANUG lesions of malnourished children than in non-ANUG, normal, and malnourished children. In Europe and the United States, ANUG affects mainly adolescents, young adults, and HIV-infected individuals, and almost never affects young children. The earlier occurrence of ANUG in Africa may be due to acquisition of HCMV in early childhood (63) and a generally impaired immune defense. ANUG in the African population studied may arise from increased rate of herpesvirus activation because of malnutrition (25) and periodontal presence of virulent bacteria (26).

Table 4. Occurrence of HCMV and EBV-1 in ANUG sites and normal periodontal sites of Nigerian children suffering from malnutritiona.

Table 4

Occurrence of HCMV and EBV-1 in ANUG sites and normal periodontal sites of Nigerian children suffering from malnutritiona.

Periodontitis in HIV-infected patients may resemble that of periodontitis of non-HIV-infected individuals, or be associated with profusely gingival bleeding or necrotic gingival tissue (35). HIV-induced immunosuppresion facilitates herpesvirus reactivation (27). Significantly more herpesviruses can be detected in gingival specimens from HIV-periodontitis lesions than from periodontitis lesions of non-HIV patients (P < 0.001) (14). HCMV occurred in 81% of the HIV-associated periodontitis lesions and in 50% of the non-HIV-periodontitis lesions; it was the most common herpesvirus identified. In HIV-positive individuals, HCMV has also been implicated in acute periodontitis (21), periodontal abscess formation and osteomyelitis (6), and refractory chronic sinusitis (86). EBV-2 was detected in 57% biopsies from HIV-periodontitis but was absent in non-HIV-periodontitis biopsies (P = 0.002). An unusually high incidence of EBV-2 in HIV-infected patients has been reported (75, 91). Loning et al. (47) found EBV DNA sequences in gingival epithelium of HIV-infected individuals, and Madinier et al. (48) detected EBV in gingival papilla specimens from 40% of HIV-infected patients and from 40% of non-HIV-infected individuals. Only one specimen of nasal, laryngeal, and oral mucosa, other than gingival mucosa, revealed EBV DNA, suggesting inflamed gingiva served as a reservoir for EBV (48). HHV-8 was detected in periodontitis lesions of 24% of HIV-infected individuals who, however, showed no clinical sign of Kaposi's sarcoma, but not in any periodontitis site of non-HIV-infected individuals. In HIV-infected patients, HCMV, EBV, HSV, and HHV-8 genomes are also generally found in saliva (7, 29) and have been related to ulcerative oral lesions (28, 37, 69, 84) and widespread gingival and mucosal inflammation (28). The clinical characteristics of HIV-associated periodontal diseases and the high rate of oral herpesviruses in HIV patients are consistent with the involvement of herpesvirus infections in these diseases.

Herpesviruses may interfere with periodontal healing as well. In a periodontal regeneration study, four periodontal sites that showed either HCMV or EBV-1 experienced an average gain in clinical attachment of 2.3 mm compared with 16 viral-negative sites that showed a mean attachment gain of 5.0 mm (P = 0.004) (80). By infecting and altering the function of fibroblasts and other periodontal cells, herpesviruses may reduce the regenerative potential of the periodontal ligament. Unrecognized herpesviral infections of the periodontium may help explain why some individuals show little or no response to periodontal regenerative treatment.

The relationship between herpesviruses and putative periodontopathic bacteria was studied in 140 adults with gingivitis or periodontitis (19). As shown in Table 5, periodontal HCMV and EBV-1 were related to elevated occurrence of the pathogens P. gingivalis, B. forsythus, P. intermedia, P. nigrescens, and T. denticola. Periodontal HCMV is also closely associated with a high rate of occurrence of D. pneumosintes and progressive periodontitis (79). Moreover, as discussed above, localized juvenile periodontitis lesions exhibiting HCMV infection tend to show elevated levels of P. gingivalis (51) and A. actinomycetemcomitans (85). The close association between periodontal herpesviruses and periodontopathic bacteria lends credence to the notion that both types of infectious agents are involved in the development of periodontitis. In the same way, evidence is emerging that otitis media (34), respiratory tract infections (5), and other nonoral infections (15) that previously were thought to be of bacterial origin might be caused by combined viral-bacterial infections (also see chapters 11 to 15). Abramson and Mills (1) suggested that viruses predispose the host to secondary infections by inducing abnormalities in adherence, chemotaxis, phagocytic, oxidative, secretory, and bactericidal activities of polymorphonuclear leukocytes, cells of major importance in controlling medical and periodontal bacterial infections (87).

Table 5. Associations between HCMV and EBV-1 and periodontopathic bacteriaa.

Table 5

Associations between HCMV and EBV-1 and periodontopathic bacteriaa.

Pathogenic Mechanisms of Herpesviruses in Periodontal Disease

Herpesviruses may cause periodontal pathosis as a direct result of the virus infection and replication, or as a result of virally induced impairment of the host defense. Herpesvirus-mediated periodontopathogenicity may take place through at least five mechanisms, operating alone or in combination.

First, herpesviruses may cause direct cytopathic effects on fibroblasts, keratinocytes, endothelial cells, inflammatory cells such as polymorphonuclear leukocytes, lymphocytes, macrophages, and possibly bone cells (17). Since the cells above are key constituents of inflamed periodontal tissue, herpesvirus-induced cytopathic effects may hamper tissue turnover and repair.

Second, gingival herpesvirus infection may promote subgingival attachment and colonization of periodontopathic bacteria similar to the enhanced bacterial adherence to virus-infected cells observed in other infections. Viral proteins expressed on eukaryotic cell membranes can act as bacterial receptors and generate new bacterial binding sites (17). Also, loss of virus-damaged epithelial cells may expose the basement membrane and the surface of regenerating cells, providing new sites for bacterial binding (17).

Third, HCMV and EBV can infect and alter functions of monocytes, macrophages, and lymphocytes in periodontitis lesions (20). As implied above, impairment of cells involved in the periodontal defense may predispose to overgrowth by periodontal pathogens.

Fourth, herpesvirus infections induce a proinflammatory response including expression of cytokines and chemokines (54). In periodontitis, herpesvirus-induced expression of cytokines is particularly intriguing. HCMV infection can up-regulate interleukin-1β and tumor necrosis factor alpha gene expression of monocytes and macrophages (17). In turn, interleukin-1β and tumor necrosis factor alpha may up-regulate matrix metalloproteinase, down-regulate tissue inhibitors of metalloproteinase, and mediate periodontal bone destruction (17). Increased production of these proinflammatory cytokines by macrophages and monocytes has been associated with enhanced susceptibility to destructive periodontal disease (61). EBV may act as a potent polyclonal B-lymphocyte activator, capable of inducing proliferation and differentiation of immunoglobulin-secreting cells, features associated with periodontal disease progression (17). Active EBV infection can also generate antineutrophil antibodies and neutropenia that may lead to increased bacterial pathogenicity and over-growth (17).

Finally, herpesviruses can produce tissue injury as a result of immunopathologic responses (52), and immunopathologic reactions have been implicated in the pathogenesis of human periodontal disease (30). HCMV can induce cell-mediated immunosuppression by down-regulating cell surface expression of major histocompatibility complex class I molecules, thereby interfering with cytotoxic T-lymphocyte recognition (52). In addition, HCMV sequesters chemokines, induces Fc receptors, interferes with induction of major histocompatibility class II antigens, inhibits natural killer cell activity, and can efficiently block the presentation of immediate early antigens, the first viral proteins to be produced (52). Moreover, HCMV can suppress antigen-specific cytotoxic T-lymphocyte functions, resulting in decreases in circulating CD4+ cells and increases in CD8+ suppressor cells, which in turn may lead to global impairment of cellmediated immunity (17). EBV may induce proliferation of cytotoxic T lymphocytes, the main purpose of which is to recognize and destroy virally infected cells, but may secondarily also hamper various aspects of the periodontal immune response (17). EBV can suppress T-lymphocyte functions as well (50). EBV-infected B lymphocytes may shed viral structural antigens that result in production of blocking antibodies, immune complex formation, and T-suppressor cell activation (39, 50). Together, these mechanisms probably contribute to the ability of herpesviruses to persist in their hosts and may play a role in immunopathology of herpesviral diseases.

Herpesvirus-Bacterium-Host Response Interactions in Periodontitis

Figure 1 describes the possible role of herpesviruses in periodontal tissue destruction. Initially, gingival inflammation induced by dental plaque bacteria causes herpesvirus-infected inflammatory cells to enter the periodontium. Subsequent herpesvirus reactivation in the gingival tissue may then aggravate the disease. Herpesvirus reactivation may occur spontaneously or as a result of various types of impairment of the host immune defense including HIV infection, pregnancy, hormonal changes, and psychosocial and physical stress. Sarid el al. (73) showed that among female students who endured stress during academic examinations, a significant increase could be detected in EBV-specific IgG and IgA salivary antibody values as well as in salivary EBV activation as measured by salivary EBV DNA or infectious virus. Factors that activate herpesviruses are also recognized risk indicators of periodontitis (72). Indeed, the reason various immunosuppressive events aggravate periodontal disease might be partially due to accompanying herpesvirus activation. Herpesvirus active infection may further diminish the resistance of periodontal tissues, thereby inducing subgingival overgrowth of periodontal pathogenic bacteria by one or more of the periodontopathic mechanisms described above. However, the interaction between herpesviruses and bacteria is most likely bidirectional, with bacterial enzymes or other inflammation-inducing products having the potential to activate periodontal herpesviruses (the vicious circle concept). In a recent study, experimental mice infected with P. gingivalis prior to infection with HCMV exhibited higher mortality rates than mice infected with P. gingivalis subsequent to HCMV infection, suggesting preexisting P. gingivalis infection increased the pathogenicity of HCMV ( J. Stern, E. Shai, A. Halabi, Y. Houri-Haddad, L. Shapira, and A. Palmon, J. Dent. Res. 80:1314, abstr. 46, 2001).

Figure 1. Herpesviruses in destructive periodontal disease.

Figure 1

Herpesviruses in destructive periodontal disease.

Herpesviral-bacterial interactions may help explain the disease characteristics of destructive periodontal disease. Alteration between prolonged periods of latency interrupted by periods of activation of herpesviral infections may be partly responsible for the burstlike episodes of periodontitis disease progression. Tissue tropism of herpesviral infections may help explain the localized pattern of tissue destruction in periodontitis. Frequent reactivation of periodontal herpesviruses may account for the rapid periodontal breakdown in some patients even in the presence of relatively little dental plaque. Absence of herpesviral infection or viral reactivation may clarify why some individuals carry periodontopathic bacteria while still maintaining periodontal health or minimal disease.

The recognition that periodontitis is a multifactorial disease involving herpesviruses, bacteria, and host defense may explain why aggressive periodontitis is relatively uncommon in most populations despite a high prevalence of individuals harboring both herpesviruses and bacterial pathogens. It might be that periodontal tissue breakdown is contingent upon the simultaneous occurrence of several infectious disease events, including (i) adequate herpesvirus load (gingivitis level) in periodontal sites, (ii) activation of herpesviruses in the periodontium, (iii) inadequate protective antiviral cytotoxic T-lymphocyte response, (iv) presence of specific periodontal pathogenic bacteria, and (v) inadequate protective antibacterial antibody response. In most individuals, these five suggested pathogenic determinants of periodontitis might come together in a detrimental constellation relatively infrequently and mainly during periods of suppressed immune response. Clearly, the importance of combined herpesviral-bacterial infections and associated host responses in the development of periodontitis needs to be studied further.

Conclusion and Perspectives

Several lines of evidence implicate herpesvirus species in the etiology and/or pathogenesis of human periodontal disease. These include the following:

  1. Presence of nucleic acid sequences of HCMV, EBV-1, and other herpesviruses in aggressive periodontitis lesions of children, adolescents, and adults
  2. Association between herpesviruses and ANUG in malnourished African children
  3. Detection of nucleic acid sequences of herpesviruses in inflammatory periodontal cells
  4. Probable profound effect of herpesviral infection on periodontal defense cells
  5. Potential of herpesviruses to augment the expression of tissue-damaging cytokines and chemokines in periodontal inflammatory cells
  6. Increased frequency of periodontopathic bacteria in herpesvirus-positive periodontitis lesions
  7. Association between periodontal HCMV-active infection and disease-active periodontitis

The notion of herpesviruses playing key roles in many types of severe periodontitis may have significant therapeutic implications. A new direction to prevent and treat periodontitis may focus on controlling disease-initiating herpesviruses. Reducing gingivitis by various antiplaque measures has been shown to diminish the herpesviral load in periodontal sites (33, 60). Future approaches to periodontal prophylaxis and treatment may include vaccination specific against herpesviruses. Thus, recent progress in studies of the importance of herpesviruses, herpesviral-bacterial interaction, and host inflammatory mechanisms in periodontitis holds great promise in leading to novel ways to prevent and cure the disease.

In addition, productive herpesviruses in inflamed gingival tissue may seed to other body sites or shed into saliva and subsequently infect other individuals. Pauk et al. (65) found that among 92 men who were HIV-seronegative but who had sex with HIV-positive men having Kaposi's sarcoma, deep kissing was an independent risk factor for infection with HHV-8. Pauk et al. (65) concluded that oral exposure to infectious saliva is a potential risk factor for the acquisition of HHV-8 among men who have sex with men and suggested that currently recommended safer sex practices may not protect against HHV-8 infection. Contreras et al. (14) detected HHV-8 in 24% of gingival biopsy samples from HIV-seropositive individuals. The data presented are consistent with the suggestion that gingival tissue is a site for herpesvirus replication, potential persistence, and a source of infective HHV-8 in saliva. Gingiva has also been proposed to constitute a reservoir for HSV (92). EBV has for decades been known to be transmitted by saliva, even among lay people who named infectious mononucleosis the "kissing disease" (31). If indeed inflamed gingiva constitutes a significant nidus for infectious herpesviruses, maintaining gingival health by professional periodontal therapy and oral hygiene measures may help reduce the risk of transmissible herpesvirus disease.

Basic research on herpesviruses may also benefit from the finding of herpesviruses in periodontal disease. During active HCMV and EBV diseases, cells of the myeloid lineage, including monocytes/macrophages and B lymphocytes, can disseminate reactivated viruses to a variety of cells and tissues. However, it is not known if epithelial cells, endothelial cells, fibroblasts, and vascular smooth muscle cells, themselves, contain latent HCMV and EBV that become reactivated or if these cells become infected de novo during active infection. One difficulty in herpesvirus research is the unavailability of readily accessible study material, especially in systemically healthy subjects having latent herpesviral infections. Since repeated viral samples can be collected from the periodontium in a noninvasive manner, herpesvirus-infected periodontal sites might constitute a valuable research model for studying the pathophysiology of herpesvirus latency and reactivation.

Clinical virology, as well, may take advantage of the frequent presence of herpesviruses in the diseased periodontium. Sampling the periodontal pocket or minor soft tissue curettage of the pocket epithelium and underlying connective tissue may help identify herpesvirus-infected individuals.


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