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JOURNAL OF CRITICAL REVIEWS

ISSN- 2394-5125 VOL 7, ISSUE 10, 2020

HERPES VIRUSES: ROLE IN PERIODONTITIS

*Dr. Paramjit Kaur Khinda1 , Dr. Dinesh Rao2 , Dr. SPS Sodhi3 , Dr. Sanjeev Salaria4

*1Faculty Periodontics, College of , KSAU-HS, Riyadh, Kingdom of Saudi Arabia; Research Scholar, Pacific Dental College, PAHER University, Udaipur, India 2Professor & Head, Department of Pediatric Dentistry, Pacific Dental College, PAHER, Udaipur, India 3Professor & Head, Department of OMFS, Dean, Dasmesh Institute of Dental Sciences & Research, Faridkot, India 4Professor & Head, Department of , Surendra Dental College & Research Institute, Sri Ganganagar, India

Abstract In the pathogenesis of severe periodontitis, there is increasing evidence regarding the involvement of herpes viral, bacterial and host immune factors but there is no clarity on the relative importance of each of these factors. Herpes viruses are re-activated by immunosuppressive factors and, maybe for this reason, they are also major risk factors for periodontitis. When the periodontitis is in a progressive phase, it seems that the inflamed is a major site for accumulation and re-activation of Epstein-Barr virus and cytomegalovirus. Matrix metalloproteinases and are activated by . Cytokines in turn are released by herpes viruses. Herpes viruses may thus act as pathogens in the progression of periodontitis. Antibacterial immune mechanisms are weakened because of an active herpesvirus infection resulting in a rise in the number of bacteria which are considered to be periodontopathogens. A suppressed herpesvesvirus infection may be re-activated by some of the periodontopathogenic bacteria. This synergy between the bacteria and herpesviruses may play a significant part in the commencement and advancement of periodontitis. Herpesvirus-induced periodontitis suggests that the immunity against herpesviruses forms a crucial feature in attaining a stable periodontium. There is a need for further investigation on the part played by herpesviruses in periodontitis which will result in enhanced diagnosis, better therapy and disease prevention. Vaccines specific to human cytomegalovirus (HCMV) and Epstein Barr virus (EBV) that shape treatment strategies against herpesvirus, may be effectively utilized in the inhibition and therapy for diseases of periodontal origin, specifically the periodontitis. Key words: herpes viruses, periodontitis, pathogenesis, bacteria

INTRODUCTION The effective management of complex pathologies like periodontitis necessitates thorough knowledge of the pathogenic processes that result in development and progression of the disease. The multifactorial nature of periodontitis comprises of an interaction between microbiological, host and environmental influences. It is generally believed that periodontitis is triggered due to certain kinds of bacteria and their metabolites. Damage to the periodontal tissue results from the collaboration among the bacterial metabolities and the host. Various studies have established that the distribution of the periodontal pathogenic bacteria does not vary greatly between subjects with and without periodontitis. Furthermore, these specific strains of pathogenic bacteria have not been isolated in every case of .1,2 Many theories have been proposed to describe the etiopathogenesis of periodontitis, but none has successfully explained the several clinical features of the disease3, such as: a) The factors responsible in the progression of to periodontitis b) The periodic character of the disease with phases of exacerbation and relative quiescence c) The site specificity of periodontitis d) Bilaterally symmetrical pattern of the disease around the midline of the mouth

The ambiguity about the infectious and clinical outcomes of periodontal breakdown has prompted to find additional etiological factors for periodontitis. Many studies3,4,10-18 have shown a connection among several of components of the herpesvirus family and periodontal disease. Epstein–Barr virus and cytomegalovirus are the viruses which have been studied extensively. A single periodontitis site may contain more than a million- herpesvirus genome-copies.4

Humans are most frequently affected by 8 of the 100 known strains of herpesviruses: virus types 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 (variants A and B), human herpesvirus 7, and human herpesvirus 8. Herpes simplex viruses 1 and 2 result in the manifestation of mucocutaneous infections. Usually they present as gingivostomatitis, dermal whitlows, herpes keratitis and herpes genitalis. Primary varicella-zoster virus infection causes varicella (chickenpox). Herpes zoster () is caused by the revival of latent virus (usually in adults). It manifests in the form of vesicular rash with a

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ISSN- 2394-5125 VOL 7, ISSUE 10, 2020 dermatomal distribution and acute neuritis. Three clinical syndromes are caused by cytomegalovirus. (1) congenital cytomegalovirus infection causes hepatosplenomegaly, involvement of central nervous system, rash and retinitis (2) primary cytomegalovirus infection causes a mononucleosis syndrome with fever, malaise, lymphocytosis and pharyngitis (3) patients who are immunocompromised, such as the ones who have had a transplant or are HIV positive, might acquire disseminated disease involving the , lungs, retina, gastrointestinal tract, and central nervous system which might be life threatening. Classic mononucleosis is caused by Epstein-Barr virus (EBV). The virus causes a lymphoproliferative syndrome in immunocompromised hosts. Epstein Barr virus causes Duncan's syndrome in some families. Exanthem subitem (roseola) is associated with human herpes viruses 6 and 7. Kaposi's sarcoma in AIDS patients as well as intra-abdominal solid tumors have been found to be associated with human herpesvirus 8.5 Most of the adults are carriers of cytomegalovirus and Epstein–Barr virus. Active lytic replication by herpes virus destroys infected cells. After primary infection, herpes viruses remain dormant with restricted manifestation of viral genes after the primary infection. But they still retain the transcriptional and replicational capacity. Human cytomegalovirus remains active in dendritic cells and in monocytes and their progenitors, Epstein–Barr virus in resting memory B lymphocytes. Innate and adaptive immune responses are elicited by active herpesvirus infections. Immune activation and immune suppression are part of these responses.6-8 Key effector cells of the comprise of the dendritic cells, monocytes ⁄ macrophages and natural killer cells. They aid in limiting the viral load till cells of the adaptive immunity take over.

Evidence for a potential role of herpes viruses in the etiology of periodontitis The viral recognition frequency among patients with and subjects who are periodontally healthy has been compared by many studies. Many of these studies have examined the relationship between the uncovering of herpes viruses and clinical parameters, that include probing depth and attachment loss. Chronic periodontitis presented with a more than 50% prevalence of herpesviruses in the affected sites.10-14 More than 50% prevalence of HCMV in the infected sites was also detected,12,15-17whereas the control group sites showed a much lesser detection of the virus.12,14-16,18-21 An association has also been reported between the presence of EBV and HCMV in relation to periodontal pathogens found subgingivally. A close relationship has also been established between the numbers of , and genome copy-counts of EBV and HCMV.22 The role of EBV-HCMV co-infection in causing severe manifestation of chronic periodontitis has also been elaborated by various studies.11,12 P.gingivalis may cause EBV reactivation via epigenetic regulation.23 In patients who have chronic periodontitis as opposed to the periodontally healthy subjects, a more common occurrence of combined infections of HCMV and T. forsythia, EBV-1 and P. gingivalis, Aggregatibacter actinomycetemcomitans and HCMV, T. forsythia and HSV-1, and P. intermedia has been seen16 (P<0.05). Betero et al15 inspected and concluded that there was an increase in , nigrescens and in HCMV-positive patients who have chronic periodontitis. They inferred that coincident infection with HCMV and elevated concentrations of periodontopathic could enhance the probability for periodontitis.

Periodontal pathogenic potential of herpesviruses Pathogenicity of herpesviruses is complex and may be carried out by direct virus infection and replication, or by altering the host immune defense. It may comprise of cytopathogenic events during the initial stages of periodontitis in immunologically immature hosts, whereas in immunocompetent individuals, most clinical manifestations are subordinate to cellular or humoral immune responses. Thus, herpesviruses either by acting alone or in association with other pathogens may be responsible for the pathogenesis of periodontal disease by multiple mechanisms, namely:  Cytopathic impact on keratinocytes, endothelial cells, fibroblasts, bone cells and inflammatory cells comprising macrophages, lymphocytes and leukocytes.24 . Viruses mediate the release of chemokines, cytokines, and other inflammatory mediators from inflammatory and noninflammatory host cells.25 The antibacterial host defense faces interference from the herpesvirus-associated proinflammatory cytokines and chemokines. This stimulates osteoclasts, promotes the activity of matrix metalloproteinases and causes decreased expression of tissue inhibitors of metalloproteinases, which in turn impedes tissue turnover and repair and increases the probability of breakdown of periodontal tissues. (PGs) are important mediators of that cause vasodilation and also induce production by different types of cells. The activity of COX-2 is promoted by IL-1β, TNF-α, and bacterial LPS. The inflamed tissues thus witness an increase in the production of PGE2 owing to the above factors. PGE2 acts as a major cause of tissue damage in the form of periodontitis by causing the induction of MMPs and osteoclastic bone resorption. . Herpesviruses may alter the immune system functions of the host. Monocytes/macrophages and T cells carry the cytomegalovirus latent genome into the periodontium whereas the EBV infects periodontal B‑lymphocytes. An increase in the virulence of periodontopathogenic bacteria like Aggregatibacter

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actinomycetemcomitans, rectus, , Prevotella nigrescens, Prevotella intermedia and Porphyromonas gingivalis can be seen due to a decrease in the expression of these cells. In cases of , EBV and HCMV have been reported very often. An association between the presence of CMV and EBV and chronic periodontitis and periodontal disease associated with systemic disease has been established by many studies.26  Pathogenecity of the periodontal microbiota may be increased by periodontal herpesviruses infection. Herpesviruses proteins expressed on eukaryotic cell membranes may act as new bacterial binding sites.27 Development of aggressive form of periodontitis can occur as CMV can augment the adherence of A. actinomycetemcomitans to primary periodontal pockets. In adult types of periodontitis, cytomegalovirus and Epstein‐Barr virus are related with P. gingivalis26. Necrotizing features of HIV- gingivitis and HIV periodontitis result due to occupation of periodontal of HIV patients by several herpes virus genera.  Herpes viruses infection may produce abnormalities in the , adherence, phagocytic and bactericidal actions of polymorphonuclear leukocytes. This is important for the restraint of periodontopathic bacteria.28  Proliferation and differentiation of B-lymphocytic stimulation happens due to Epstein–Barr virus active infection inducing anti-neutrophilic and neutropenia24  The pathogenic mechanisms of different herpes viruses act together in aggravating the disease. Thus, in severe form of periodontitis, a periodontal twin infection with HCMV and EBV29, or with HCMV and herpes simplex virus30, tends to happen.  HCMV may induce cell mediated immunosuppression by decreasing the cell surface expression of major histocompatibility complex class I molecules. This interrupts the cytotoxic T lymphocyte recognition leading to further suppression of the generation of major histocompatibility class II inhibiting natural killer cell action. Furthermore, a reduction in circulating CD4+ cells and an increase in CD8+ suppressor cells is caused by HCMV causing impairment of specific cytotoxic T lymphocyte function.

Slots31 described a pattern of periodontitis, at the centre of which is an infectious process that alternates between bacteria to herpes viruses to bacteria. The dental contains bacteria which often lead to gingival inflammation, which in turn promotes easy entry of herpes viruses infected inflammatory cells present in the DNA of T lymphocytes and B lymphocytes as well as macrophages into the periodontal tissues. The ensuing revival of the herpes viruses in the tissues of gingiva may be unprompted or a result of weakening of the immune defense systems. Examples are HIV infection, physical and psychosocial stress, and hormonal alterations which are known risk factors of periodontal diseases.

T-cell-mediated immune response is mediated by the host, comprising largely of CD8+ T cells in reply to the active herpes virus infection. The herpes viruses in turn perform various strategies to reduce the expression and activation of host defenses which are antiviral. Herpes viruses often escape the immune responses by causing disintegration of the elements of the MHC by suppressing natural killer cells, obstructing antigen presentation, deflecting cytokine responses, forcing out IL-10, and stopping apoptosis. This interaction between defenses of the host and virally mediated anti-host responses lead to release of pro-inflammatory cytokines. These have the ability to stimulate osteoclasts and damage -mediated host defenses against bacterial species, such as A. actinomycetemcomitans and P. gingivalis. Surplus mechanisms of periodontal tissue damage are imparted due to this resulting proliferation in pathogenic bacteria. A cytopathogenic effect can be seen on keratinocytes, epithelial cells, fibroblasts, inflammatory cells, endothelial cells and bone cells by the action of cytomegalovirus or other herpes viruses. In immunocompromised patients, herpesviral infection may promptly destroy periodontal tissue by cytotoxic mechanisms, examples can be found in patients who have and necrotizing ulcerative gingivitis. Herpesviral‑bacterial exchanges may help explain the burst‑like events characteristic of periodontitis. This episodic nature of periodontal disease may be attributed to alternating periods of lengthy latency and periods of activation of herpesviral infections. Preservation of periodontal health despite the presence of pathogenic bacteria in the periodontium can be attributed to the absence of herpesviral infection while its frequent reactivation justifies the rapid periodontal breakdown observed in a few patients despite good and relatively little . Localized pattern of tissue destruction in periodontitis may be explained by tissue tropism of herpes viral infections.

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ISSN- 2394-5125 VOL 7, ISSUE 10, 2020

Herpesviral-bacterial model of periodontitis (Slots 2010)

Therapeutic Implications The treatment of severe forms of periodontitis by conventional periodontal therapy which is built upon the model of bacterial etiology has not been very effective. The herpes viral–bacterial concept of periodontitis provides an insight for reflecting upon new therapeutic pathways to prevention of disease as well as treatment. Periodontal therapy involving antibacterial and antiviral agents could prove to be a valuable treatment strategy in patients with refractory and recurrent periodontitis. Sunde et al32 treated a patient with refractory periodontitis and high EBV with valacyclovir hydrochloride which resulted in noticeable recuperation of the periodontal condition of the patient. The antiviral drugs are well tolerated without any significant adverse effects. Ahead of the anti-herpes viral chemotherapy being counted as standard clinical practice for the treatment of advanced periodontitis, the randomized controlled trials are required. In order to achieve a long- lasting state of steady periodontium, immunity against herpes virus may constitute an important aspect. That the diseased periodontal sites are a prominent home of salivary herpes viruses has been proposed by many studies33- 36. The periodontal therapy aimed at decreasing herpes virus concentrations in may facilitate in reduction of the chance of herpes virus transmission and herpes virus-related diseases between close associates. High priority is being assigned to the development of vaccines against Epstein Barr virus, herpes simplex virus, and cytomegalovirus, especially for administration to 12-year-old children.

Conclusion Available evidence suggests the herpes viruses are involved in the etiopathogenesis of periodontitis by a number of mechanisms. Further research on the part of herpes viruses in periodontitis is needed for better diagnosis, precise therapy and disease prevention. Treatment strategies against herpes viruses, including possible vaccination, may be effectively used in the prevention and treatment of periodontitis.

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Sources of Support: None Conflict of Interest: None

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