the process of evolution has shaped viruses towards the same objective as other organisms , that is , survival and procreation . as with any obligate parasite , a winning strategy requires not just efficient replication , but also a means of transmission between hosts . consequently it is not an optimal strategy to kill the host ; in fact , it is generally preferable to reside in an active , implying not very sick , host . one feature that distinguishes viruses is their extreme form of what in biology is referred to as r - selection. the term is used for organisms that produce as much progeny as possible without bothering about quality assurance or putting resources into each one of them . this strategy allows the virus to have more sloppy machinery for rna or dna replication than any other cellular organisms ; viruses can afford to make thousands of worthless copies of themselves for each competent viral particle . the point is a nightmare for clinicians , in that viruses relatively easily develop resistance to antiviral medication , and in that they escape vaccines or the immunological memory of previous infections . although viruses as a rule of thumb are best served by having a healthy host , they can still cause serious disease . three factors are of particular importance for the clinical outcome of a viral infection . for one , viruses that have a long evolutionary history with a particular host generally have evolved mechanisms to avoid unnecessary damage to their host , while viruses that recently jumped from one species to another have not had the chance to do so . consequently , zoonotic viruses pose a particular threat to human health . the second factor is whether the virus is inclined to remain with the host for a long time , preferably throughout the life - span , or if it is more of a  hit - and - run virus . in the latter case the third factor is whether the virus requires particular behaviour of the host in order to be transmitted to another individual ; coughing is perhaps the most obvious and well - known example . in table 1 , viruses can infect any type of cell in human body , with the possible exception of erythrocytes ; still the mouth has a particular significance . for one we breathe , drink and eat every day ; thus all that is required for the virus is a strategy that allows transmission either through air or through water / food . the former is typically cared for by the infected host when he coughs and thus sends out aerosols containing viral particles ; the latter is reflected in transmission by the faecal  oral route , that is , the virus infects the guts and is thus released to the environment through the faeces . in order to pursue these strategies , viruses are not required to replicate in the mouth , and most viruses do not . for various reasons they prefer , respectively , the respiratory system or the intestines , consequently the concomitant disease is typically restricted to these organs . in certain cases , however , replication in the mouth may be preferable . humans are not the only species that have developed a delight in kissing , but probably no other species are prone to engage in the exchange of sputum to the extent that we humans are . not surprisingly , certain viruses apparently have adapted to this behaviour in their approach to the issue of transmission . in order to assure viral presence in sputum , it is preferable to replicate in cells lining the oral cavity and release a continuous stream of viral particles . herpesviruses and papillomaviruses are among the viruses that presumably use this strategy . obviously , replication in oral tissue places the oral cavity more at risk for clinical symptoms . herpesviruses have a double - stranded dna genome and are among the largest and most complex human viruses . there are eight members of the human herpesvirus ( hhv ) family ( table 2 ) . the more common , as to oral health problems , are the two herpes simplex viruses ( hsv-1 and -2 ) , which cause recurrent herpetiform ulcerations referred to as cold sores . these ulcers typically occur on the lips , but the viruses can also cause similar lesions in the mucosa , such as in the case of gingivostomatitis . the mucosal affection is normally associated with a primary herpes infection in children , and is accompanied by bodily symptoms such as fever and malaise . both hsv-1 and -2 may be involved in oral manifestations , although the latter is primarily associated with the genitals . epstein - barr virus ( ebv ) and cytomegaloviruses ( cmv ) are present in the vast majority of adults , but in most cases probably without ever causing any overt disease . both can , however , cause mononucleosis ; ebv being responsible for most of the cases . mononucleosis is also known as  kissing disease , suggesting that the virus spread through direct mouth - to - mouth contact . the condition is common at puberty , and is considered a consequence of the host not having been in contact with the virus earlier in life . ebv 's potential for affecting the mouth is further underlined by oral hairy leukoplakia , i.e. white patches typically on the side of the tongue with a hairy appearance , a rare condition restricted to immunosuppressed patients . varicella - zoster virus ( vzv ) is associated with chicken pox , as a primary infection , and with herpes zoster if reactivated later in life . the vesicular rash formed occurs primarily in the skin , but may also affect the mucosa . the three remaining human herpesviruses ( hhv-6 , -7 and -8 ) rarely cause serious disease , but the former two are responsible for a particular type of rash ( roseola ) with associated fever in infants . hhv-8 is presumably responsible for kaposi 's sarcoma , a rare form of skin cancer seen in immunosuppressed patients . the herpesviruses typically form chronic infections where the virus remains with its host till death do them apart ; much of the time in latency , but with occasional bursts of activity . as these viruses are contact transmitted , either by means of virus production in the skin accompanied by rashes and blister or viral presence in sputum , it is not surprising to find viral activity in the oral cavity . in addition to the traditional clinical picture referred to above , two of them in particular , ebv and cmv have been associated with periodontitis ( recently reviewed in reference ( 6 ) ) . several laboratories have demonstrated that these viruses are found significantly more frequently in samples taken from affected pockets compared to healthy pockets ( 710 ) , however , this association does not necessarily mean that they are involved in the pathology . ( 7 , 8) , suggest that these viruses can influence the development and course of periodontitis , while others are more sceptical , partly due to the low numbers of virus observed ( 9 , 11 , 12 ) . periodontitic lesions may , in part , be the transmission strategy for these viruses , particularly cmv , as replication in the lesions allows viruses to reach the saliva and thus potentially infecting other individuals ( 13 ) . one should be careful when evaluating the presence of low levels of viral genomes in clinical samples as an indication of a viral role in pathogenesis . ebv and cmv are known to be occasionally found in any mouth , as long as a relevant sample of sufficient size is analysed by a sensitive technique . ebv in particular is known to be cyclically active in the body and periodically present in sputum . thus , the mere presence of viruses in the absence of signs of local viral activity , either in the form of high viral titres or detection of viral rna or proteins , probably do not constitute any appreciable impact on the aetiology . moreover , associations such as between viruses and particular bacterial species , or between viruses and the severity of the condition , may be explained by confounding factors ; for example , a more active inflammation would be expected to correspond to the presence of particular bacteria , and cause more pain , but also to contain more lymphoid cells and/or more body fluids . the latter factors could explain the association with herpesviruses as both ebv and cmv replicate in leukocytes . the observation that a patient recovered from a chronic and highly treatment refractory periodontal condition upon antiviral treatment ( 500 mg valacikolovir , valtrex , orally 2 over 10 days ) may be the single most - relevant data suggesting an occasional clinical role for these viruses in periodontitis ( 14 ) . the initial viral load in this patient was considerably higher than what was observed in any of the other patients tested . both the clinical condition and the viral load remained stable , and close to the detection level , during a one - year follow - up period after the antiviral treatment . although the amount of sample obtained from the various teeth examined was not standardised , and is expected to be smaller when obtained from healthy pockets , the sampling differences can neither explain the three log increase in initial viral load compared to other patients , nor the five to six log drop in viral load observed after treatment . more cases utilising similar antiviral treatments are necessary to provide statistical significance to implicate a potential role of viruses in periodontitis . antiviral treatment seems to be the best way to shed light on the actual role of ebv or cmv in periodontitis . moreover , if successful , it may save the patients from considerable pain and agony . we therefore believe that quantitative antiviral tests , such as real - time pcr , are relevant in the management of these patients , maybe particularly in juvenile and/or chronic and aggressive cases for which other therapy fails . if the tests find appreciable amounts of virus , or other signs of local viral activity , antiviral treatment should be considered as an adjunct to conventional periodontal therapy . it should be noted that the latter form of therapy has also been reported to reduce the viral load ( 15 ) . herpesviruses are well known for their capacity to manipulate the immune system . although the obvious purpose of manipulation is to boost viral replication , it is easy to envision that a down - regulation of immunological surveillance may also benefit other agents present , such as bacteria . the issue , in regard to periodontitis , has been recently reviewed by slots ( 16 ) . briefly , viral activity in periodontal tissues may impact the local immune response in a way that benefits opportunistic bacteria , and thus leads to aggravated symptoms . for example , the viruses produce cytokine mimics designed to modulate the host 's immune defence it should be noted that the microbial activity can also induce viral replication , as has been shown recently in the case of ebv and malaria ( 17 ) . if the impact of viral replication on the bacterial environment is real , then it might be expected that the bacterial profiles would differ between sites with or without virus . human papillomavirus ( hpv ) is a dna virus that can cause chronic infection of either skin or mucosal epithelium . parts of the viral genome are occasionally integrated in the dna of the host cells , and some of the genes are assumed to have a malignant potential , as reviewed in reference ( 18 ) . the role of hpv in cervical cancer is well accepted and has led to the widespread use of papillomavirus vaccines for young women ; related carcinomas occur in the mouth cavity as well as in the oropharyngeal area , however , the role of hpv is less obvious in these cases ( 19 ) . based on their putative role in cervical carcinoma , the viruses are classified as having either high ( primarily 16 and 18 ) or low ( primarily 6 and 11 ) oncogenic potential . although the reported prevalence varies considerably , hpvs are common in oral samples such as biopsies or brush samples of mucosa , indeed one laboratory reported that 95% of superficial scrapes from healthy mouths were positive ( 20 ) . although hpvs are also found in biopsies from healthy mouths , their prevalence is typically reported to be higher in biopsies from oral lesions such as leukoplakia or cancers . in the former case , the association with oncogenic hpvs is less obvious ; while in the case of malignant cancers most laboratories find a definite overrepresentation of the more malignant hpvs ( 1922 ) . the observed prevalence of oral cancers are , however , considerably lower than those reported for cervical cancers . still the case favouring a role of these viruses is reasonably strong . in future , as those who receive papillomavirus vaccines grow up , it will be interesting to see whether the prevalence of oral carcinomas declines along with the expected decline in cervical cancer . in fact , it has been argued that the vaccines should also be offered to men , partly because they too are at risk for genital cancer , and partly due to the assumed connection with oral cancer ( 23 ) . the main argument against vaccinating both sexes is that these forms of cancer have a considerably lower prevalence in males compared to cervical cancer in females . as the virus forms chronic infections , vaccination of individuals who already contain the potentially malign subtypes nevertheless , it seems reasonable , however , to make the vaccine available at an early age to both sexes . enteroviruses have a single - stranded rna genome and are classified into five species with all together more than a hundred subtypes . although the majority of human enterovirus ( hev ) infections are asymptomatic , they can cause upper respiratory illness , febrile rash , aseptic meningitis , pleurodynia , encephalitis , acute flaccid paralysis and neonatal sepsis - like disease ( 24 ) . as to oral affection , this is a febrile illness with tender papulovesicular lesions of both the hand , feet and oral mucosa ( 25 , 26 ) . the association with enteroviruses primarily concerns the type a viruses , e.g. coxsackie virus a16 and enterovirus-71 , but other enteroviruses may also be involved . herpangina is a related condition where the clinical manifestation is primarily in the oral cavity in the form of ulceration and blisters . this is partly because of an increased awareness that viruses are possible aetiological agents , and partly because the methods of viral detection have become considerably easier . the preferred methods are based on variants of real - time pcr , which not only offer a test for the viral presence , but also yield quantitative data . the latter point is particularly relevant as several of the viruses in the oral cavity may be prevalent even in healthy mouths . a high viral load in a sample taken from affected tissues may , however , as a rule of thumb , suggest direct involvement in the underlying condition . one problem is that several viruses that are chronically present in the body can replicate in leukocytes ( e.g. ebv and cmv ) . as the typical clinical samples will stem from inflamed tissues , such as periodontal pockets or ulcerations , one would expect a presence of these viruses ; if for no other reason due to the accumulation of leukocytes ; a point that has been demonstrated at least in the case of cmv and periodontitis ( 27 ) . again , a clinical role is suspected if the titre is particularly high , and even more so if the condition improves upon antiviral treatment . in order to take samples for detection of viral nucleic acids , whether by pcr or other methods , it is preferable to immediately transfer the sample to a small tube containing lysis buffer . the lysis buffer will block the bacterial activity and stabilise the viral rna and dna present . the tubes are advised to be frozen unless the samples are to be tested within a day or two , in which case they may be kept in the refrigerator . upon arrival in an analytical laboratory , rna and/or dna are extracted from the samples , and aliquots added to a reaction mix for pcr . whether the samples consist of saliva , brush scrapings from mucosa , dental plaque or subgingival plaque , both the actual amount of sample and the content , e.g. contaminants from blood , can vary considerably . theoretically , one might correlate the presence of virus with other markers in the sample , such as bacterial 16s rrna or human genes , but that does not offer a convincing standardisation . it seems that the best option is to be careful as to adding relevance to minor amounts of virus , or small differences between samples ; however , major differences such as in the antiviral treatment study ( 14 ) can not be due to sampling variations . a main limitation of pcr - based methods is that they only detect the viruses they are designed to detect . several novel human viruses have appeared during the last decade , and most likely the human body is the host to a range of viruses that are yet to be described . moreover , the cost of the methods restricts analyses to a few viral species ; thus the total spectrum of potentially relevant viruses is rarely tested . two recent strategies compensate for this limitation : microarrays and pyrosequencing . in microarrays , probes detecting different viruses ( or other agents ) can be applied to a slide and the sample dna or rna hybridised onto the slide , thus offering the possible detection of all known viruses . in pyrosequencing , the complete nucleic acids present in the sample are sequenced to look for recognisable viral sequences by searching relevant databases . both these methods have the same , twofold limitations : one , they are less sensitive than pcr ; and two , they are considerably more expensive , although the costs for pyrosequencing is becoming more cost - efficient . thus , these techniques are not useful for routine diagnostics , but they may be valuable when investigating a possible viral cause of unknown conditions . although various viruses have been implicated by the association ( 28 ) , it seems unlikely that the true viral culprit , if any , is yet to be found . there is no conflict of interest in the present study for any of the authors .
the focus has traditionally been on bacteria and fungi when discussing microbiological aspects of oral disease . 
 viruses are probably more involved in diseases associated with the oral cavity than has been previously thought . 
 the role of several viruses in ulceration is well known , but viruses of the herpes family may play a role in periodontitis , and papillomaviruses are probably involved in oral cancer . this review offers a brief introduction to virology before discussing the role of the more relevant viruses in oral disease . as to clinical application , it is concluded that the anti - herpes medication may , in some cases , be relevant in treating periodontitis , while papillomavirus vaccine would be expected to decrease the prevalence of oral cancer .