HIV infection and periodontal diseases: an overview of the post-HAART era
M Mataftsi1, L Skoura2, D Sakellari3
1Private Practice;2Department of Microbiology, Medical School, Aristotle University of Thessaloniki;3Department of Periodontology, Dental School, Aristotle University of Thessaloniki, Thessaloniki, Greece
HIV infection remains a global health problem of unprecedented dimensions, although the development of highly active antiretroviral therapy (HAART) has signifi- cantly modified the course of HIV disease into a man- ageable chronic disease with longer survival and improved quality of life in HIV-infected subjects. Among the HIV-associated infections, oral lesions have been recognized as prominent features since the beginning of the epidemic and continue to be important. Periodontal diseases strongly associated with HIV infection are clas- sified as linear gingival erythema, necrotizing ulcerative gingivitis and necrotizing ulcerative periodontitis and are included among the cardinal oral lesions. Although oral candidiasis appears to be the infection more significantly decreased after the introduction of HAART, the current literature suggests that the prevalence and course of periodontal lesions have also been modified. Higher prevalence of opportunistic microorganisms has been frequently detected in the subgingival flora of HIV- infected individuals, probably due to the immune status of those patients, as colonization and overgrowth of atypical pathogenic species is facilitated by immuno- suppression. Additional research is required regarding biological issues such as the role of oral immune factors and periodontal disease in the persistency of HIV infec- tion, the possibility of oral transmission and the re-emerging of HIV infection.
Oral Diseases (2011) 17, 13–25
Keywords: HIV; periodontitis; highly active antiretroviral therapy
HIV infection remains a global health problem of unprecedented dimensions. Unknown 27 years ago, HIV has already caused an estimated 25 million deaths
worldwide and has generated profound demographic changes in the most heavily aﬀected countries. While the percentage of people living with HIV has stabilized since 2000, the overall number of people living with HIV has steadily increased, as new infections occur each year, HIV treatments extend life and in addition, new infections still outnumber AIDS deaths.
The development of highly active antiretroviral ther- apy (HAART) especially after 1995, has signiﬁcantly modiﬁed the course of HIV disease, at least in the industrialized world, into a manageable chronic disease with longer survival and improved quality of life in HIV-infected subjects.
HAART generally consists of a dual nucleoside analogue reverse transcriptase inhibitor (NRTI) Ôback- bone’ and a third or Ôcornerstone’ drug, such as a non- nucleoside inhibitor (NNRTI) or a protease inhibitor (PI), usually a Ôboosted’ one. The use of a NNRTI as a third drug is less potent and therefore, in most settings not a preferred option and it is recommended that baseline resistance testing should guide the speciﬁc regimen design.
HAART increases CD4 + cell count, decreases levels of HIV RNA and extends AIDS-free survival, at least in the short-term. Moreover, HIV suppression with antiretroviral therapy may decrease inﬂammation and immune activation thought to contribute to higher rates of cardiovascular and other co-morbidities reported in HIV-infected cohorts.
Eradication of HIV infection cannot be achieved with available antiretroviral regimens. This is mainly attrib- uted to the fact that the pool of latently infected CD4 + T-cells is established during the earliest stages of acute HIV infection and persists with a long half-life, even with prolonged suppression of plasma viraemia.
It is known that HAART is associated with signiﬁcant problems, including toxic side eﬀects, development of virological resistance and great ﬁnancial expense. Up to half of patients on antiretroviral therapy may experience adverse eﬀects of the medications (Fellay et al, 2001).
Common side-eﬀects vary depending on the drug regimen, but can include hypersensitivity, lactic acidosis,
Correspondence: Dimitra Sakellari, Assistant Professor, Department of Periodontology, Dental School, Aristotle University of Thessaloniki 54124, Greece. Tel: +30 2310 999565, Fax: +30 2310 999613, E-mail:
Received 2 February 2010; revised 5 May 2010; accepted 11 May 2010
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increases in blood lipids, bleeding events, anaemia, neuropathy, lipodystrophy and pancreatitis (UNAIDS, 2008). While most side-eﬀects diminish over time, some can be life-threatening, underscoring the importance of careful patient monitoring (UNAIDS, 2008).
Due to the intensity of combined antiretroviral treatment and widespread use of HAART, the incidence of many AIDS-related opportunistic infections in patients with advanced HIV infection has signiﬁcantly decreased but despite dramatic declines in the incidence of opportunistic infections in many resource-rich nations, opportunistic infections remain a leading cause of hospitalization and death for persons with HIV infection.
Among the HIV-associated infections, oral lesions have been recognized as prominent features of HIV infection since the beginning of the epidemic and continue to be important.
Purpose of the present review is to overview the features, prevalence, bacteriology and host response characteristics of periodontal infections in HIV patients, especially as modiﬁed during the HAART era.
Features of periodontal lesions in HIV-infected patients
HIV infection in adults is linked with the expression of various types of periodontal lesions, which include speciﬁc forms of gingivitis and necrotizing periodontal diseases, as well as with possible exacerbation of preex- isting periodontal disease (Winkler and Robertson, 1992;
EC-Clearinghouse, 1993; Robinson, 2002). Periodontal diseases strongly associated with HIV infection are classiﬁed as linear gingivitis erythema (LGE), necrotizing ulcerative gingivitis (NUG) and necrotizing ulcerative periodontitis (NUP) and are included among the seven cardinal oral lesions, which have been identiﬁed and recognized internationally, as follows: oral candidiasis, oral hairy leukoplakia Kaposi sarcoma, LGE, NUG, NUP and non-Hodgkin lymphoma (EC-Clearinghouse, 1993; Armitage, 1999; Coogan et al, 2005).
The criteria for diagnosis of HIV-related oral lesions are not well deﬁned in children. Orofacial manifesta- tions have been categorized into three groups: those less commonly, commonly and strongly but rarely associ- ated with pediatric HIV infection. LGE has been reported between those commonly associated (Ramos- Gomez et al, 1999; Coogan et al, 2005).
Together with other oral infections, HIV-associated periodontal diseases are regarded as serious complica- tions of HIV infection and have an important diagnostic and prognostic value (EC-Clearinghouse, 1993; Glick et al, 1994a; Shangase et al, 2004; Coogan et al, 2005).
They belong among the earliest clinical features of the infection and could predict progression of HIV disease to AIDS (Robinson, 2002; Coogan et al, 2005). It should also be mentioned that for patients on antiret- roviral therapy, HIV-related oral lesions in general, may suggest possible treatment failure as will be further discussed in the present review (Margiotta et al, 1999;
Eyeson et al, 2002; Gaita´n-Cepeda et al, 2005; Flint
et al, 2006; Ramı´rez-Amador et al, 2007). However, HIV-associated periodontal infections are less common than oral candidiasis and oral hairy leukoplakia and thus not included as criteria in the Centers for Disease Control (CDC) classiﬁcation (CDC, 1992). HIV-associ- ated periodontal infections have characteristic clinical appearance which has been well described (Winkler and Robertson, 1992; Murray, 1994; Reznik, 2006; Green- span and Greenspan, 2008).
Linear gingival erythema (LGE) is a form of gingivitis characterized by a distinct ﬁery red band along the margin of the gingiva (EC-Clearinghouse, 1994). It is usually associated with anterior teeth, commonly extended to the posterior teeth, accompanied in some cases by bleeding and discomfort (Reznik, 2006). In other cases it presents as petechia-like patches on attached or free gingiva. Currently, Candida species have been implicated to the aetiopathology of LGE as well as other HIV-associated periodontal pathology.
Necrotizing ulcerative gingivitis (NUG) is character- ized by rapid onset and acute painful inﬂammation of gingiva with rapid destruction of soft tissues, while necrotizing ulcerative periodontitis (NUP) is escorted by bleeding, sharp pain, ulcerated gingival papillae, rapid and extensive soft tissue necrosis and advanced loss of periodontal attachment, frequently leading to bone exposure (Murray, 1994; Reznik, 2006; Greenspan and Greenspan, 2008).
The rapid establishment and course of necrotizing forms of periodontal disease in patients with HIV⁄ AIDS infection, contrary to the gradually progressing peri- odontal disease in adults in the general population has been outlined in many studies and had not been reported before AIDS epidemic (Murray et al, 1989;
Barr et al, 1992; Yeung et al, 1993a; Murray, 1994).
HAART appears to have profoundly inﬂuenced the prevalence, severity and course of periodontal lesions as will be further discussed in the next section of the present review (Parveen et al, 2007).
Risk factors for periodontal disease in HIV-infected individuals besides the general factors of age, smoking, preexisting gingivitis, poor oral hygiene and poor diet, include counts of CD4 + cells (Glick et al, 1994b), viral load and speciﬁc species of microbiota.
Oral opportunistic infections, mainly oral candidiasis (OC) and oral hairy leukoplakia (OHL) have been associated with CD4 + count in both the pre-HAART and the HAART era in several studies. Based on these ﬁndings, low CD4 + counts are now considered as the main risk factor associated with the development of oral lesions and especially of oral candidiasis (Margiotta et al, 1999).
Regarding periodontal disease, there is little and unclear data, especially during the HAART era. In 1994, Glick et al have reported an association between NUP and CD4 + count below 200 cells mm)3in HIV- infected patients and suggested that NUP may be a good marker of immune deterioration. The same authors reported in another 1994 study a positive predictive value (95.1%) for periodontal diseases, which was higher than the values reported for oral hairy leukopla-
kia (70.1%) and oral candidiasis (69.9%) (Glick et al, 1994a). High positive predictive values have also been reported for necrotizing ulcerative periodontitis (80%) and a moderate (54.5%) one for LGE (Begg et al, 1996;
Patton, 2000). In agreement with the previous studies, Margiotta et al (1999) reported that NUP and NUG were signiﬁcantly associated with CD4 + counts lower than 200 cells mm)3 in a cohort of Italian subjects infected with HIV. In contrast to these reports, Schu- man et al, in a study conducted in a US population, after the introduction of HAART, reported that LGE and NUG were not related to HIV serostatus or CD4 + lymphocyte count (Schuman et al, 1998).
Contradictory results have also been reported in a 2000 study by Patton. The author reported that the viral load was signiﬁcantly related to the presence of strongly HIV-associated oral lesions (Patton, 2000) but that among periodontal lesions, only LGE has a signiﬁcant predictive value (70%) for immune suppression when measured by CD4 cell counts below 200 cells mm)3. In the same study, the predictive value for necrotizing ulcerative diseases was lower (47.4%) compared to the values reported previously, a ﬁnding which could be attributed to the improved antiretroviral management of HIV disease of the population under investigation. A signiﬁcant correlation between necrotizing ulcerative diseases and CD4 + T cells number below 200 mm)3 was also reported in a study from South Africa, with a positive predictive value of 69.6% for HIV infection in otherwise asymptomatic subjects (Shangase et al, 2004).
As HIV infection gradually becomes a chronic disease, the features and course of chronic periodontal disease in HIV infected patients require more extensive investiga- tion. The Ôconventional’ periodontal diseases in the HAART era have been mentioned in very few studies (Alpagot et al, 2004; Kroidl et al, 2005). Conventional periodontitis progresses gradually, causing no or minimal pain or discomfort, being thus undiagnosed, until con- siderable tissue loss occurs (Alpagot et al, 2004). Gener- ally, periodontal inﬂammation seems to be more severe in cases where CD4 + counts are low (Kroidl et al, 2005) and research nowadays is focused on the accelerated rate with which chronic adult periodontitis presents in sero- positive patients (Lamster et al, 1997).
Overall, ﬁndings from the above mentioned studies suggest the value of the identiﬁcation of periodontal disease, even in patients on HAART therapy, in screening the immune suppression, both in diagnosed and undiagnosed HIV infection in adults.
The relation between oral lesions in general and immune and virologic status is still not well established in children. No association was found between the prevalence of oral lesions and immunological status or viral load in children, while there are no data for periodontal diseases (Gaita´n-Cepeda et al, 2002).
Prevalence of periodontal diseases in HIV- infected individuals
The prevalence of periodontal diseases in HIV-infected individuals remains a controversial issue. Data from
relevant studies vary widely due to several factors. Many studies refer to HIV-infected individuals, without men- tioning the stage of AIDS or the use and the type of antiretroviral therapy, the use of protease inhibitors or not, as well as the use of adjuctive antimicrobials (antibiotics, antifungals). Factors which inﬂuence the prevalence of periodontal disease such as age, immune system competence, smoking habits, oral hygiene level, are not always taken into consideration (Barr et al, 1992; Alpagot et al, 2004). The type of lesion is often not mentioned, while there is some confusion with the terminology. Additionally, it is usually unclear whether diagnosis is made by trained examiners or if universally accepted criteria are used (EC-Clearinghouse, 1993).
Introduction of antiretroviral therapies and mainly the HAART in 1995 has changed the epidemiology of opportunistic infections in HIV-infected patients (Holt- zer et al, 1998; Paul et al, 2002) and has decreased the mortality and morbidity of HIV infection (Palella et al, 1998). A signiﬁcant decrease of the overall prevalence of oral lesions from 47–85%, before the introduction of HAART, to 32–46%, post-HAART has been reported (Patton et al, 2000; Schmidt-Westhausen et al, 2000;
Gaitan Cepeda et al, 2008). Oral manifestations signif- icantly decreased in patients on dual and triple therapy in comparison with patients on monotherapy and those on no antiretroviral therapy (Tappuni and Fleming, 2001). Moreover, a lower prevalence (32%) of oral lesions was found in patients on HAART, including efavirenz, compared to patients on HAART including a PI (63%). (Aquino-Garcı´a et al, 2008). Recently, in a retrospective epidemiological analysis performed in Brazil from 1988 to 2004, HAART was found to be associated with signiﬁcantly lower prevalence of oral manifestations (Ferreira et al, 2007). Among oral man- ifestations, oral candidiasis appears to be the lesion most signiﬁcantly decreased after the introduction of HAART as shown by several studies.
Regarding the prevalence of HIV-associated peri- odontal diseases in the pre-HAART era, data vary widely both in developed and developing countries.
Indicatively, reported rates of prevalence for LGE range between 9 and 50%, for NUG between 11 and 25% and for NUP between 1 and 18% (Tukutuku et al, 1990;
Laskaris et al, 1992; Masouredis et al, 1992; Glick et al, 1994b).
After the introduction of HAART, ﬁndings from relevant studies also vary and cannot be compared, partly because of the diﬀerent types of therapy received by participating patients. Data from representative studies in developed and developing countries concern- ing adult and paediatric populations are shown in Table 1. The eﬀect of HAART on prevalence of HIV- associated periodontal disease is shown in Table 2. It appears that HAART is associated with a lower prevalence of HIV-associated periodontal disease in adults. The diﬀerence between pre- and post-HAART in most of the studies was found to be statistically signiﬁcant.
On the contrary, HAART does not appear to signiﬁcantly aﬀect the prevalence of periodontal disease
HIV-associatedperiodontaldiseaseConventional LGENUGNUPGINGPERIO Adults Schumanetal(1998)USA867HIV+35%onART13.6%11.6% Pattonetal(2000)USA606HIV+30%onHAART⁄PI3.3%NUG⁄NUP=3.1% Ceballos-Salobren˜a etal(2000)Spain154HIV+100%onHAART0.6%0.6% Eyesonetal(2002)UK203HIV+69%onHAART6%8%3% Reichartetal(2003)Thailand, Cambodia87HIV+63HIV+none onHAARTThai–8% Cambodian–12%Thai0% Cambodian–27.7% Pinheiroetal(2004)Brazil161HIV+70.8%onARTPeriodontaldisease=4.4% Kroidletal(2005)Germany139HIV⁄AIDS100%onHAART9%NUG⁄NUP=3.6%28%30% Bravoetal(2006)Venezouela75HIV+63%onART52%on HAART8% Ranganathanetal(2004)India774HIV+11%onART72%33% GaitanCepedaetal(2008)Spain86HIV⁄AIDS100%onHAART0%0%0%0%0% Bradyetal(1996)USA25HIV⁄AIDS84%52% Ceballos-Salobren˜a etal(1996)Spain396HIV+Periodontaldisease 78.3% Alpagotetal(2004)USA152HIV+patients63%on HAART19%73% Children Santosetal(2001)Brazil80HIV+17.5% Khongkunthianetal(2001)Thailand45HIV+33.3%onART2.2% Gaita´n-Cepedaetal(2002)Mexico48HIV+Periodontal⁄gingivaldisease4.2% Reichartetal(2003)Thailand45HIV+33%onART2.2% ART:anytypeofantiretroviraltherapy;HAART:highlyactiveantiretroviraltherapy;HAART⁄PI:highlyactiveantiretroviraltherapywithproteaseinhibitorasthethirddrug;GING:gingivitis; PERIO:periodontitis;LGE:lineargingivalerythema;NUG:necrotizingulcerativegingivitis;NUP:necrotizingulcerativeperiodontitis.
HIV-associatedperiodontaldisease EffectoftherapyLGENUGNUP Aguirreetal(1999)Spain72HIV+patients CD4+<499 onHAART
48.6%31.9%LGEaredown, NUPhasremainedsteadyincomparison totwoearlierstudiesfromtheSpain Schmidt-Westhausen etal(2000)Germany103HIV+patients 1monthonHAART1.9%.2.9%After6monthsoftherapy,from61 re-examinedpatientsonlyonehadNUP Pattonetal(2000)USAPre-HAART,271HIV+ 8%onHAART Post-HAART,299HIV+ 42%onHAART.
4.8% 1.7%SigniﬁcantdecreaseofNUP (P=0.03) Ceballos-Salobren˜a etal(2000)Spain154HIV⁄AIDS onHAART⁄PI foratleast6months
0.6%0.6%Morethan30%decreaseofHIV associatedperiodontaldiseasein comparisonwithhistoricalcontrols TappuniandFleming (2001)UK195HIV+notonART 89HIV+onART6% 2%DecreaseofNUG Ramı´rez-Amadoretal (2003)BrazilStudyof12years beforeHAART (1989–1995) afterHAART (1996–2001) Periodontaldisease 4.1%(1989–1991) 1.7%(1992–1995) 0.4%(1996–1998) 0.7%(1999–2001) Signiﬁcantdecreaseofperiodontaldisease betweenbeforeandafterHAART periods (P=0.002) Ferreiraetal(2007)Brazil1230HIV+ (1988–2004) onHAART
2.5%1.6%1.3%HAARTassociatedwithasigniﬁcant lowerprevalenceofLGE(P<0.001) Nicolatou-Galitisetal (2004)GreeceHIV+notonART HIV+ondoubleARTandHAART⁄PI8.1% 0%DecreaseofNUG HAART:highlyactiveantiretroviraltherapy;,HAART⁄PI:highlyactiveantiretroviraltherapywithproteaseinhibitorasthethirddrug;ART:anytypeofantiretroviraltherapy.HIV-accociated periodontaldisease:LGE:lineargingivalerythema;NUG:necrotizingulcerativegingivitis;NUP:necrotizingulcerativeperiodontitis.
in children (Flanagan et al, 2000; Khongkunthian et al, 2001; Parveen et al, 2007).
Bacteria associated with periodontal disease in HIV-infected patients
The development of periodontal disease is generally accepted to depend on the interaction between the host response and the resident oral microbiota, which con- stitutes a complex dynamic bioﬁlm of multiple microbial communities. Considering that it is a microbial com- munity disease, a distinct microbial proﬁle in these patients, if identiﬁed, could assist our understanding of the aetiopathological mechanisms (Kuboniwa et al, 2009).
Results from studies on the subgingival microbiota in HIV-infected individuals are quite diverse. Some studies have shown that the microbiota is similar in HIV- positive and HIV-negative patients with periodontitis (Zambon et al, 1990; Brady et al, 1996; Nakou et al, 1997; Teanpaisan et al, 2001; Tsang and Samaranayake, 2001). Other studies have shown a higher prevalence of putative periodontal pathogens such as Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, Por- phyromonas gingivalis, Prevotella intermedia, Tannerella forsythia and Treponema denticola, in HIV-positive patients, in comparison to HIV-negative patients (Mur- ray et al, 1989; Cross and Smith, 1995; Scully et al, 1999; Alpagot et al, 2004), while there are studies that present the exact opposite, i.e. that putative pathogens are less prevalent in HIV-positive patients. (Tenenbaum et al, 1997; Paster et al, 2002; Patel et al, 2003; Botero et al, 2007; Gonc¸alves de Souza et al, 2007).
Several authors agree that certain microbial species such as Candida spp. (Jabra-Rizk et al, 2001), Enterob- acter faecalis (Zambon et al, 1990; Nakou et al, 1997;
Gonc¸alves de Souza et al, 2004, 2007), Clostridium clostridiiforme(Zambon et al, 1990) Clostridium difﬁcile (Zambon et al, 1990; Nakou et al, 1997; Gonc¸alves Lde et al, 2007), Klebsiella pneumoniae (Zambon et al, 1990; Nakou et al, 1997; Botero et al, 2007; Gonc¸alves de Souza et al, 2007), Mycoplasma salivarium (Zambon et al, 1990; Moore et al, 1993; Nakou et al, 1997;
Gonc¸alves de Souza et al, 2007), Pseudomonas aerugin- osa(Nakou et al, 1997; Botero et al, 2007; Gonc¸alves de Souza et al, 2007), Acinetobacter baumanii (Nakou et al, 1997; Gonc¸alves de Souza et al, 2007), Enterobacter cloacae (Nakou et al, 1997; Botero et al, 2007), which are frequently found in the periodontal environment of HIV-positive patients, are uncommon in other individ- uals. The role of these Ôuncommon’ species in the pathogenesis of periodontal disease in HIV-infected individuals is not yet fully understood, while it is suggested that the higher prevalence of such opportu- nistic micro-organisms is due to the immune status of those patients as colonization and overgrowth of atyp- ical pathogenic species is facilitated by severe immuno- suppression (Gonc¸alves de Souza et al, 2004).
Data from studies in the HAART era, which apply culture-independent molecular techniques are displayed in Table 3. These techniques as well as other approaches
such as proteomics and the study of bioﬁlms will allow an extensive investigation of the microbiota in HIV- infected individuals and the pathogenetic role of Ôunusual’ species.
As shown in Table 3, bacteria that are not usually linked with periodontal disease, such as Enterococcus faecalis, Acinetobacter baumanii, Pseudomonas aerugin- osaand Campylobacter pylori, were frequently detected in HIV-infected patients, in most of the studies (Gon- c¸alves de Souza et al, 2004, 2007; Gonc¸alves de Souza et al, 2009; Aas et al, 2007). Putative periodontopatho- genic bacteria, such as T. forsythia, P. gingivalis, P.
intermedia, were associated with periodontitis (Alpagot et al, 2004; Gonc¸alves de Souza et al, 2004) in HIV- positive patients and were considered as risk factors (Gonc¸alves de Souza et al, 2004), whereas in many studies the prevalence of these classical periodontopath- ogenic bacteria was found smaller in HIV-positive than in HIV- negative subjects (Paster et al, 2002; Patel et al, 2003; Aas et al, 2007; Gonc¸alves de Souza et al, 2007;
Gonc¸alves de Souza et al, 2009). Possibly, pathogens such as P. gingivalis, that are commonly associated with periodontal disease, do not consist the principle path- ogenic factor, while both atypical oral organisms and typical periodontopathogenic bacteria inﬂuenced the pathogenesis of periodontitis in HIV-infected patients.
Moreover the recognition of diﬀerent microbial pro- ﬁles in the subgingival area of these patients may be signiﬁcant. More complex microbial proﬁles were dem- onstrated in diseased sites than in healthy periodontium in HIV-infected patients (Paster et al, 2002), while certain combinations of microbes were detected exclu- sively in HIV-infected individuals. These speciﬁc Ôcom- plexes’ may be responsible for chronic periodontitis in this group of patients (Patel et al, 2003) since it is known that changes in the humoral and cellular immunity can aﬀect the establishment and growth of pathogens and the resultant combination of microbes in the subgingival pockets of HIV-positive subjects.
HIV–host interaction in the periodontal environment Periodontal disease may result from a loss of regulation of immune responses to oral microbiota (Jotwani et al, 2001).
However, in HIV-infected patients, pathogenetic mechanisms involved in immune responses and in tolerance at the oral mucosa in health and inﬂammation remain unclear and studies are required in order to deﬁne the interaction between the immuno-compro- mised host and microbes. In general, it is poorly understood how HIV or HIV-infected cells aﬀect oral mucosal epithelium and inﬂuence innate and acquired immunity and how the altered local or systemic immune response of these patients contributes to the pathogen- esis of periodontal disease (Alpagot et al, 2004; Challa- combe and Naglik, 2006). Subgingival bioﬁlm micro- organisms have the capacity to activate inﬂammatory cells including polymononuclears (PMN), lymphocytes and macrophages, which produce inﬂammatory media- tors and subsequently induce MMPs and their inhibitors production. It is known that, in periodontal disease,
Table3StudiesofsubgingivalplaquemicrobiotainHIV-infectedpatientsinHAARTerausingculture-independentmethods AuthorsSubjectsampleMethodologyPrincipalﬁndings Pasteretal(2002)8HIV+⁄NUP HAART:datanotavailableCheckerboardDNA hybridizationassay Over200probes
108speciesidentiﬁed(65uncultivable) Mostfrequent:Bulleidiaextructa,Dialister,Fusobacterium, Selenomonas,PhylumTM7 Peptostreptococcus,Veillonella, Classicalperiodontalpathogensnotdetected Differentandmorecomplexmicrobialproﬁles inperiodontitisthaninhealthyperiodontium Pateletal(2003)20HIV+⁄CP HAART:datanotavailablePCRforPnigrescens,C.rectus, P.intermedia,Pgingivalis, T.denticola,E.corrodens, A.actinomycetemcomitans
T.denticolaandP.gingivalislessprevalentinHIV+subjects ThreemicrobialproﬁlesexclusivelyinHIV+ P.nigrescens⁄C.rectus P.nigrescens⁄P.gigivalis P.nigrescens⁄T.denticola Alpagotetal(2004)152HIV+⁄CP 63%HAARTFluorescentassayforselective Gram-negativespeciesF.nucleatum,P.intermedia,A.actinomycetemcomitans, P.gingivalis:riskfactorsforperiodontitisinHIV+ Gonc¸alvesdeSouzaetal(2004)64HIV+⁄CP 100%HAARTCheckerboardDNAhybridization assay Probesfor22species SeveralclassicalpathogensmoreprevalentinHIV+⁄CPthan inHIV+⁄healthyperiodontium:E.faecalis,F.nucleatum moreprevalentinpatientswithlowerTCD4+cells Gonc¸alvesdeSouzaetal(2007)37HIV+⁄CP 35HIV+⁄HP 100%HAART
CheckerboardDNAhybridization assay Probesfor33species
Bacterialspeciesandclassicalperiodontal pathogenslessfrequentinHIV+⁄CP,thanin HIV)⁄CP(T.forsythia,S.gordonii.P.gingivalis, S.intermedius,) UnusualforCPspeciesmorecommonlyin HIV+(A.baumannii,E.faecalis) Aasetal(2007)14HIV+⁄CP,gingivitis,LGE HAART:datanotavailable16Sand18SrRNA-cloningand sequencing109species(42%uncultivable)wereidentiﬁed Gemella,Dialister,Streptococcus,Veilonellawerepredominant Classicalperiodontalpathogensnotdetected(T.denticola, P.gingivalis,T.forsythia) UnsualforCPmicrobes(Pseudomonas,Neisseria)more commonlyinHIV+andsevereimmunosupression Gonc¸alvesdeSouza etal(2009)13HIV+⁄CP 10HIV+⁄HP 100%HAART
PCRfor H.pylori,E.faecalis,P.aeruginosaUnusualforCPmicrobesmorefrequentin CPthaninhealthyperiodontium(E.faecalis, E.pylori,P.aeruginosa) E.pylorimostprevalentinCPinHIV+ CP:chronicperiodontitis;NUP:necrotizingulcerativeperiodontitis;HP:healthyperiodontium;HAART:highlyactiveantiretroviraltherapy;LGE:lineargingivalerythema.
most of the tissue damage is caused by host response (Lamster and Novak, 1992; Van Dyke and Serhan, 2003). In HIV-infected patients with periodontitis an increase of inﬂammatory mediators has also been detected. Alpagot et al (2003) reported that the higher GCF levels of pro-inﬂammatory cytokine interferon-c (IFN-c) is associated with the periodontal disease progression in HIV-positive patients similarly to reports for non-HIV individuals with chronic periodonditis (Dutzan et al, 2009). High levels of signiﬁcant mediators of inﬂammation involved in the pathogenesis of peri- odontal disease such as prostaglandin E2(PGE2) (Lei- bur et al, 1999), transforming growth factor-beta (TGF- b1), matrix metalloproteinase -1 (MMP-1) were also found in gingival cervicular ﬂuid (GCF) of periodontitis sites in HIV⁄ AIDS patients and could serve as prog- nostic factors for the progression of tissue destruction in HIV-infected adults.
After the introduction of HAART, HIV-infection is considered as a chronic infection characterized by persistency of the virus in the infected host and, despite the undetectable plasma levels of the HIV, cessation of therapy results in viral reappearance in circulation (Chun et al, 1999). Persistency of the virus is possibly due to a very low level of replication and continuous secretion of virus by long-lived infected cells, undetect- able by conventional assays or HIV latency and silenc- ing (reviewed in Williams and Greene, 2007; Mok and Lever, 2008; Colin and Van Lint, 2009; Dahl et al, 2009).The oral cavity seems to be an important reservoir of HIV-1 as the virus is found in saliva, GCF and oral epithelial cells. To date, HIV-1 reservoirs have been identiﬁed in the reproductive tract, breast, lung, brain and gastrointestinal tract (Schrager and D’Souza, 1998) Therefore, the role of oral immune factors and periodontal disease in the persistency of HIV infection, the possibility of oral transmission and the re-emerging of HIV infection, should be investigated.
The oral cavity has rarely been reported as a site of HIV transmission (Klein et al, 1988; Cohen et al, 2000;
Jotwani et al, 2004; Cutler and Jotwani, 2006). In saliva, HIV is present at very low levels (Spear et al, 2005) possibly due to low levels of macrophages and lympho- cytes and to inhibitory factors in the saliva of HIV- infected patients. A number of host defence factors are present in the saliva including, the hypotonic nature of saliva (Baron et al, 1999), endogenous inhibitors of HIV, particularly secretory leucocyte protease inhibitor (SLPI) that blocks HIV infection in several cell-culture systems (Shugars et al, 1999), salivary mucins MUC5B and MUC7 which trap and aggregate the virus and can inhibit it by 100% (Habte et al, 2006), sIgA antibodies which neutralize HIV, antimicrobial peptides such as a- and b-defensins (Nakashima et al, 1993; Zhang et al, 2002; Mackewicz et al, 2003; Quin˜ones-Mateu et al, 2003; Jotwani et al, 2004), histatins (Groot et al, 2006) and lactoferrin. It seems that the inhibitory factors may act synergistically (Bolscher et al, 2002).
Recently, HIV-speciﬁc antibody dependent cell-med- iated cytotoxicity (ADCC) activity, an important part of cell mediated immunity, was demonstrated in saliva.
(Kim et al, 2006). Moreover, studying the possible eﬀect of microbial components on HIV, inhibition of virus entry by a binding domain (HGP44) of P. gingivalis was demonstrated (Xie et al, 2006).
HAART appears not to adversely aﬀect inherent salivary oral host defence in HIV-patients with mild to moderate immune dysfunction (Lin et al, 2006).
In many studies RNA (Shugars et al, 2001; Spear et al, 2005) and DNA of HIV have been detected in saliva (Levy and Greenspan, 1988; Goto et al, 1991;
Yeung et al, 1993b). Possible sources of infectious virions and proviral HIV-1 DNA in saliva include serum and HIV-containing macrophages and lympho- cytes from GCF, which is increased during periodontal infection. In most studies, HIV is present in patients’
saliva at very low levels, lower than blood. However, Shugars et al (2001) reported that ﬁve out of 67 HIV- positive subjects expressed higher levels in saliva than blood and also had more advanced HIV-associated periodontal disease, suggesting that HIV can be pro- duced locally in the oral cavity and may be inﬂuenced by oral tissue inﬂammation.
Although, relatively little and contradictory informa- tion on HIV excretion patterns in GCF is available in the literature, however the presence of periodontitis may be a contributing factor. Proviral HIV-1 DNA, viral RNA and p24 antigen has been detected in up to 50% of GCF samples from HIV-infected subjects with peri- odontitis (Sanz et al, 1996; Chebbi et al,1997; Maticic et al, 2000) while in some reports the virus or the p24 antigen have not been detected in GCF samples (O’Shea et al, 1990; Chebbi et al, 1997). These results suggest that infected mononuclear cells present in GCF could be a potential source of HIV-1.
More over it has been demonstrated that HIV-1 infects and replicates in vitro in keratinocytes isolated from normal oral mucosa (Moore et al, 2003) as well as in vivo in oral mucosal epithelial cells (Rodrı´guez-In˜igo et al, 2005), which could represent a reservoir for the virus, although this is not a universal ﬁnding (Quin˜ones- Mateu et al, 2003).
Regarding gingival tissues, studies have shown that dendritic cells (DCs) and macrophages in gingiva express C-type lectin receptors DC-SIGN (Dendritic- cell-speciﬁc ICAM-3-grabbing non-integrins, CD209), MR (mannose receptors, CD206) and Langerin (CD 207), which are targets for HIV and other microbes (Van Kooyk et al, 2004). Using these receptors HIV could advance by down-regulating intracellular signalling and eﬀective immune response and cause chronic infections that persist for life. However, recent studies showed that, during health, in lamina propria cells usually express the DC-SIGN receptors and mannose receptors, but very few of the cells present the CCR5 on their surface and none present the CXCR4 HIV co-receptors (Jotwani et al, 2004). In the epithelium, cells do not express CD4 but instead glycospingolipid-galactosyl- ceramide (GalCer) and Langerin receptors (Jotwani et al, 2004; Challacombe and Naglik, 2006). HIV co- receptors CCR5 and⁄ or CXCR4 were found closer to the basal layer far from the surface-associated layers
(Jotwani et al, 2004). So, in health, low expression of CCR5, and restricted expression of CXCR4 in oral mucosa suggest an unfavourable environment for the virus and this may play a signiﬁcant role in the resistance of gingiva to infection with HIV-1 (Jameson et al, 2002; Jotwani et al, 2004).
In the presence of inﬂammation, there is evidence of up-regulation of various receptors, including HIV recep- tors, on the surface of oral epithelium and the epithelium may become more permeable (Challacombe and Naglik, 2006). Moreover, in patients with chronic periodontitis there is a signiﬁcant increase in the number of dermal dendritic cells (DDCs) expressing DC-SIGN receptors and a trend for increased mannose receptors identiﬁed in the inﬂamed gingival lamina propria (Jotwani et al, 2004). It is suggested that HIV uses both the above C-type lectin receptors to attach to diﬀerent dentritic cells subsets (Turville et al, 2001). It has been shown that dentritic cells, DDCs and LCs, form immune conjugates with CD4 + T cells in the lamina propria (Jotwani and Cutler, 2003) and under these conditions it is possible for dendritic cells to transfer HIV in the T-lymphocytes in the inﬂammed gingival lamina propria.
It has also been reported that in the presence of oral lesions and periodontal disease there is a continuous shedding of HIV-infected blood into the oral cavity from mucosal and gingival lesions in HIV-infected patients, resulting in the detectable presence of the HIV at a high frequency in the oral cavity, with an increased possibility for HIV transmission (Bolscher et al, 2002).
According to the above mentioned ﬁndings, inﬂam- mation is considered as a risk factor for HIV infection, although defensive mechanisms. However, during chronic periodontitis there is a 10-fold increase in a-defensin-1 (Jotwani et al, 2004), known to have potent anti-HIV activity, while HBD2 and HBD3 are also up- regulated during inﬂammation (Dale, 2002; Quin˜ones- Mateu et al, 2003).
Notably, co-infection with the endogenous pathogen P.gingivalis in vitro, revealed an upregulation of CCR5 receptors of oral keratinocytes, which are not usually expressed in health, through LPS stimulating the toll- like receptors (TLRs) and gingipains. The R5-type HIV- 1 co-receptors CCR5, is the target of R5-type HIV-1 associated with most primary systemic infections. Thus infection with P. gingivalis could increase transmission of HIV infection through the oral cavity (Giacaman et al, 2007).
In addition, periodontal diseases and other oral opportunistic infections in HIV-infected patients could inﬂuence HIV reactivation. They represent chronic infections and associated inﬂammation, with a possibil- ity of latently infected host cell stimulation. Transcrip- tion of the HIV-provirus is dependent on the interaction between cellular and viral transcription factors (reviewed in Williams and Greene, 2007; Mok and Lever, 2008). The mechanisms involved in the reactiva- tion of latency remain to be elucidated, however a number of factors such as diﬀerent cellular environ- ments and long terminal repeat (LTR) variations in
diﬀerent HIV-1 isolates have been proposed that may play a role (Rohr et al, 2003).
In vitroexposure of latently infected resting CD4 + cells to a number of cytokines, bacterial antigens, mitogens or monoclonal antibodies directed to T-cell receptors CD3 can induce viral replication, but these ﬁndings have not been reproduced in vivo. It is also suggested that in the progress of an opportunistic infection micro-organisms or their components, such as LPS, stimulate and activate TLRs and subsequently NFjB and other transcription factors. In addition, transcription factors can be activated indirectly by the large amounts of pro-inﬂammatory cytokines and chemokines which are produced during infection (reviewed in Gonza´lez et al, 2009). Regarding perio- dontal pathogens, it has recently been shown that P. gingivalis produces high concentrations of butyric acids causing histone acetylation which is involved in repressing HIV transcription and results in virus persis- tency (Imai et al, 2009). The results of the study and the above mentioned possible mechanism of reactivation of HIV, suggest that periodontal disease could act as a risk factor for HIV reactivation in infected individuals and might contribute to the systemic dissemination of the virus.
This hypothesis could be the biological basis linking a chronic infection such as periodontitis to the Ôimmune reconstitution inﬂammatory syndrome’ (IRIS) (Gaitan Cepeda et al, 2008) a situation in which, pre-existing asymptomatic or mildly symptomatic infections or inﬂammatory conditions paradoxically worsen with a substantial increase in inﬂammation during the initial months of host immune reconstitution, as a result of HAART (Feller et al, 2007; Murdoch et al, 2007).
Opportunistic oral infections have not yet been characterized as IRIS, but Nicolatou-Galitis et al (2004) and Greenspan et al (2004) have reported a lack of reduction of oral lesions despite a higher mean CD4 + count and a lower mean viral load, with HAART treatment. Recently, Gaitan Cepeda et al (2008) found that HIV+⁄ AIDS patients under HAART who present CD4 + lymphocyte counts of >500 cells ml)1 and undetectable viral loads can suﬀer opportu- nistic oral HIV-associated infections. IRIS may lead to increased frequency of periodontal disease as the pres- ence of latent infection(s) has been considered as a risk factor for the syndrome (Crum-Cianﬂone, 2006; Mur- doch et al, 2007). However, it is not known if the appearance of these lesions is the consequence of a qualitative failure of immune cell response or examples of de novo infections.
The introduction of HAART has signiﬁcantly modiﬁed the course of HIV disease, at least in the industrialized world, into a manageable chronic disease with longer survival and improved quality of life in HIV-infected subjects. Oral lesions are among the clinical manifesta- tions whose prevalence, severity and course have been aﬀected by this treatment. Although oral candidiasis
appears to be the infection more signiﬁcantly decreased after the introduction of HAART, the current literature suggests that the prevalence and course of periodontal lesions have also been modiﬁed. Additional research is required regarding biological issues such as the role of oral immune factors and periodontal disease in the persistency of HIV infection, the possibility of oral transmission and the re-emerging of HIV infection.
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