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Periodontal disease in HIV-infected adults in

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microbiological aspects

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Review

Periodontal disease in HIV-infected adults in the HAART era:

Clinical, immunological, and microbiological aspects

Lucio Souza Goncalves a,*, Barbara Mulatinho Lopo Goncalves b,

Tatiana Vasconcellos Fontes a
a
Dental School, Estacio de Sa University, Rio de Janeiro, Brazil
b
Private Dental Pratice (Center for Integrated Dentists), Brazil

article info abstract

Article history: The introduction of highly active antiretroviral therapy (HAART) has decreased the inci-
Accepted 13 May 2013 dence and prevalence of several oral manifestations such as oral candidiasis, hairy leuko-
plakia, and Kaposis sarcoma in HIV-infected patients. Regarding periodontal disease the
Keywords: findings are not clear. This disease represents a group of chronic oral diseases characterized
Highly active antiretroviral therapy by infection and inflammation of the periodontal tissues. These tissues surround the teeth
HIV infection and provide periodontal protection (the gingival tissue) and periodontal support (periodon-
Periodontal diseases tal ligament, root cementum, alveolar bone). Clinical, immunological, and microbiological
Microbiology aspects of these diseases, such as linear gingival erythema (LGE), necrotizing periodontal
Immunology diseases (NPD) (necrotizing ulcerative gingivitis [NUG], necrotizing ulcerative periodontitis
[NUP] and necrotizing stomatitis), and chronic periodontitis, have been widely studied in
HIV-infected individuals, but without providing conclusive results. The purpose of this
review was to contribute to a better overall understanding of the probable impact of HIV-
infection on the characteristics of periodontal infections.
# 2013 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386

2. Periodontal diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386
3. Periodontal disease in HIV-infected individuals . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386
3.1. Linear gingival erythema. . . . . . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1386
3.2. Necrotizing periodontal diseases . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1387
3.3. Chronic periodontitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1387
4. Prevalence of periodontal disease in HIV-infected individuals. ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388
5. Immunological aspects of periodontal disease in HIV-infected patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1388
6. Periodontal microbiota in HIV-infected patients. . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1389
7. Final comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1392
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1393

* Corresponding author at: Rua Dois de Dezembro, 78, Sala 913, Flamengo, CEP: 22.220-040 Rio de Janeiro, RJ, Brazil. Tel.: +55 21 22053425;
fax: +55 21 22256813.
E-mail addresses: luciogoncalves@yahoo.com.br, luciogoncalves0512@gmail.com (L.S. Goncalves).
00039969/$ see front matter # 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.archoralbio.2013.05.002
1386 archives of oral biology 58 (2013) 13851396
1. Introduction
In recent years, human immunodeficiency virus (HIV)/ac-
quired immunodeficiency syndrome (AIDS), characterized by
a rapidly progressive immunodeficiency course leading to
death, has become a manageable chronic condition and have
significantly improved the life of HIV infection individuals as a
consequence of the introduction and use of HAART since
1996.1 HIV-infected individuals are living longer and develop-
ing non-HIV-related chronic conditions similar to the rest of
the population.2 This therapeutic regimen is known as highly
active antiretroviral therapy (HAART), which consist of
combination of at least three antiviral drugs, preferably from
at least two different classes. As today there are several drug
combinations, HAART has been defined as one or more NRTIs
combined with a PI and often supplemented with one drug
from another class3.
HAART has decreased the viral load and has reduced
morbidity and mortality related to AIDS. The mortality index
has fallen from 97.4% in 1993 to 19.8% in 2001.4 Furthermore,
after the introduction of HAART, there was a significant
decrease of opportunistic infections in HIV-infected patients,5
including oral manifestations such as oral candidiasis, hairy
leukoplakia, Kaposis sarcoma, herpes simplex and periodon-
tal disease.69 However the impact of these changes in
periodontal disease is less clear.10
Previous studies reported that HIV-infected patients have
an increased risk of developing more aggressive periodonti-
tis.1113 Recent studies however have not confirmed these
findings.1419 In fact, the establishment of HAART may have
provided a protective effect, keeping the pathogenic sub-
gingival microbiota of these subjects under control, even in a
condition of severe immunosuppression.20 In addition, evi-
dence has shown that protease inhibitors may also inhibit
proteinases of other microorganisms such as species of
Candida.21 Although HAART has decreased the incidence
and severity of atypical forms of periodontal diseases, such as
linear gingival erythema (LGE) and necrotizing periodontal
diseases (NPD) in HIV-infected individuals,22 with regard to
chronic periodontitis, these factors need to be clarified.23
Therefore the objective of this study is to perform a review of
the literature on periodontal diseases in HIV-infected adults.
2. Periodontal diseases
Periodontal disease represents a group of chronic oral diseases
characterized by infection and inflammation of the periodon-
tal tissues. These tissues surround the teeth and provide
periodontal protection (the gingival tissue) and periodontal
support (periodontal ligament, root cementum, alveolar bone)
(Fig. 1). The colonization of oral bacteria on the surface of a
tooth leads to the formation of a dental biofilm, which can
harbour pathogenic species (periodontal pathogens). These
microorganisms initiate an inflammatory response in the
gingival connective tissue resulting in gingivitis. However if
the inflammatory process continues, it can result in a chronic
non-reversible inflammatory state of the supporting struc-
tures.24 The detection of these subgingival microorganisms,
Fig. 1 Periodontal tissues: gingiva, periodontal ligament,
root cementum, and alveolar bone.
such as classic periodontal pathogens (Porphyromonas gingiva-
lis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia,
Treponema denticola, etc.) as well as others species (Eubacterium
nodatum, Porphyromonas endodontalis, Prevotella tannerae, Filifac-
tor alocis), has been performed by the utilization of molecular
techniques such as DNA/DNA chequerboard analysis, cloning,
polymerase chain reaction (PCR). These molecular technolo-
gies also provide new resources to identify not only single
microorganisms, but communities with potential pathogenic
importance.25
The progress of the periodontal disease establishes con-
ditions for the destruction of collagen fibres and root surface
attachment as well as resorption of alveolar bone, with
consequent loss of teeth if periodontal treatment is not
performed.26 Although periodontal diseases are initiated by
bacterial species living in biofilms at or below the gingival
margin, it is the intensity of the host response to microbial
challenge that seems to be responsible for tissue destruction,27
with a Th-1 response more related to gingivitis and a Th-2 to
periodontitis (EFP). However, animal experimental studied
have shown that distinct microorganisms result in different
rates of bone loss. In fact, combinations of periodontal
bacterial species have been shown to have synergistic effects
on tissue destruction. In addition, studies have shown a direct
influence of different bacterial complexes on gene and protein
expression in periodontal tissues and conceivably on clinical
phenotypes.25
3. Periodontal disease in HIV-infected
individuals
3.1. Linear gingival erythema
LGE was first described by Winkler and Murray.28 This lesion is
defined as an intense linear erythema, most frequently found
in anterior teeth, accompanied in some cases by bleeding and
discomfort. It normally manifests in immunosuppressed
individuals.2830 The development of oral candidiasis31 can
 archives of oral biology 58 (2013) 13851396
Fig. 2 Linear gingival erythema (LGE) and pseudomembranous candidiasis in the bottom of the maxillary vestibule in HIV-
infected patient.
be associated with subgingival colonization of Candida
species32 and LGE (Fig. 2). The aetiology of this oral disease
seems to involve an invasion by Candida species of the
gingival tissue. A histopathological study comparing lesions of
LGE in HIV-infected patients with advanced gingivitis and in
non HIV-infected individuals showed an increase of polymor-
phonuclear leukocytes and IgG in the first lesion, while the
second lesion demonstrated a predominance of T lympho-
cytes and macrophages.33 Polymorphonuclear leukocytes are
recognized by their activity in the control of Candida infection
after tissue invasion by these microorganisms. It has been
proposed that the inadequate activity of polymorphonuclear
leukocytes could be responsible for the persistence of Candida
infection in immunodeficient individuals.34 These findings
justify the classification of LGE as a gingival disease of fungal
origin.29 It is unclear if LGE may progress to a more severe
periodontal disease, although there is a suspicion that this oral
disease could be representative of an initial stage of NPD in
HIV-infected patients. Of interest, Patton35 showed that LGE
has a significant predictive value (70%) for immune suppres-
sion at CD4+ T lymphocyte counts <200 cells/mm3, while the
predictive value for necrotizing ulcerative diseases was <50%.
These results demonstrate the importance of early diagnosis
of LGE in HIV-infected patients.
3.2. Necrotizing periodontal diseases
NPD refer to necrotizing ulcerative gingivitis (NUG), necrotiz-
ing ulcerative periodontitis (NUP) and necrotizing stomatitis
Fig. 3 Necrotizing ulcerative gingivitis (NUG) with necrosis
of the gingival papilla between teeth 3233 and 3231 in
HIV-infected patient.103
This figure is being reproduced with permission from the
Quintessence International.
1387
(NS).36,37 These conditions occur often in patients with
suppressed or compromised immune systems.3840 NUG is
limited to gingival tissue without loss of periodontal clinical
attachment (Fig. 3), while NUP involves periodontal ligament
and alveolar bone destruction (Figs. 4 and 5). Patients may also
have fever, malaise, bad breath or lymphadenopathy.41 The
expression of NPD in HIV-infected patients can occur at
different levels of immunodeficiency.41 CD4+ T lymphocyte
counts <500 cells/mm3 have been correlated with the pres-
ence of NUG.34,39,42 Other authors reported that HIV-infected
individuals with NPD are 20.8 times more likely to have CD4+ T
lymphocyte counts <200 cells/mm3 than patients without
these lesions.43 Nevertheless, recent study with 84 individuals
(43 HIV-infected not undergoing antiretroviral therapy) from
the Ga-Rankuwa district in South Africa showed no statisti-
cally significant association between extent or severity of
NUG/NUP.44
The introduction of antiretroviral therapy at the beginning
of the 90 s has been credited with extending the life span of
people living with HIV/AIDS. A significant reduction in the
frequency and incidence of many events secondary to HIV
infection, such as opportunistic infections6 and NPD22,45 has
been observed. Nevertheless, several authors have recently
reported cases that may represent progression of previously
quiescent disorders to symptomatic diseases after initiation of
highly active antiretroviral therapy (HAART). Such cases have
been referred to as immune reconstitution inflammatory
syndrome (IRIS) or immune reconstitution disease.46,47 Even
though the prevalence of NPD in the HIV-infected population
undergoing HAART is low it can develop as a clinically
aggressive and painful condition. A better understanding of
the etiopathogenesis of these diseases is necessary for
determining more adequate preventative and therapeutic
strategies.
3.3. Chronic periodontitis
Although HAART has reduced the incidence and severity of
some clinical forms of periodontal diseases, such as LGE and
NPD in HIV-infected individuals,22 its impact on chronic
periodontitis (CP) is not clearly documented.23 In the pre-
HAART era, studies of CP in HIV-infected individuals showed a
greater clinical severity, mainly in severe immunodeficiency
conditions, than in non HIV-infected individuals.11.12,48,49 Barr
et al.11 reported that the risk for periodontal attachment loss
may be six times higher in HIV-infected subjects over 35 years
1388 archives of oral biology 58 (2013) 13851396
Fig. 4 Necrotizing ulcerative periodontitis (NUP) with
exposed bone among teeth 31, 32 and 41 in HIV-infected
patient.103
This figure is being reproduced with permission from the
Quintessence International.
of age with CD4+ T lymphocyte counts <200 cells/mm3. Similar
findings were observed by other researches.13,48,49 Further-
more, high levels of viral load in the plasmatic serum and
crevicular fluid have been associated with an increase of
periodontal attachment loss.12
After the introduction of HAART there was an increase in
life span in this population and consequently many individu-
als with pre-existing periodontitis experienced a higher
clinical attachment loss due to increasing age.23 Nevertheless,
before the introduction of HAART, Robinson et al.50 reported
an increased attachment loss without pocketing as a condition
frequently seen in HIV-infected individuals, resulting from
past episodes of ulceration. More recently, Goncalves et al.17
demonstrated that the long-term use of HAART in Brazilian
HIV-infected individuals resulted in a decrease in the severity
of CP, although Fricke et al.19 observed no differences in the
periodontal status of HIV-infected patients with and without
antiretroviral treatment. In a recent study an association
between periodontal clinical parameters (clinical attachment
levels and probing pocket depth) CD4+ T lymphocyte levels
was not observed.15
In a cohort study conducted in HIV-infected Senegalese
individuals not undergoing antiretroviral therapy and with
periodontal disease, a significantly higher prevalence of
individuals with clinical attachment levels 6 mm was
observed in HIV-infected individuals than in the non HIV-
infected control group.51 Despite this, it is unclear how
antiretroviral therapy can impact the clinical parameters of
CP in HIV-infected individuals and further studies are needed
to confirm these findings.
Fig. 5 Clinical aspect of necrotizing ulcerative
periodontitis (NUP) after peridontal therapy with great
bone loss among teeth 11, 12 and 13.
4. Prevalence of periodontal disease in HIV-
infected individuals
Pioneering studies that evaluated periodontal disease in HIV-
infected patients had serious methodological problems that
hampered the epidemiological characterization of periodontal
disease in this population, since it selected inappropriate
control groups and therefore presented selection bias.
Furthermore the lack of definitive diagnosis criteria for these
lesions contributed to the wide variation of reports for these
prevalence studies.34 The reports of LGE prevalence, for
instance, ranged from 0 to 50%.34,50,52,53 However most of
the studies with greater methodological rigour reported a
prevalence of LGE as less than 10% before HAART introduc-
tion.22,40 The prevalence of NUG and NUP also demonstrated
variations, but most of the studies demonstrated less than a
5% incidence of these lesions.22,40 In a study of 584 Brazilian
individuals living in the State of Rio de Janeiro, Silva et al.54
found a NUP prevalence of 6.3%. In another study performed
by Bertazzoli et al.55 of 109 Brazilian individuals living in
Campinas, LGE was observed in 34% and NUP in 20% of
individuals examined. Both studies were based only on the
clinical description of the lesion. In a study of 1012 Brazilian
HIV-infected individuals, LGE, NUG and NUP were observed in
2.5%, 1.6% and 1.3% of the examined individuals, respective-
ly.56
Since the advent of HAART, a significant decrease of
periodontal lesions has been seen. Ceballos-Salobrena et al.57
studied the prevalence of oral lesions in HIV-infected patients
undergoing HAART and have reported that the combined
prevalence of LGE, NUG and NUP was from 0.6%. Nittayananta
et al.58 did not find LGE in individuals with long-term HAART.
However, others studies have not shown such a significant
reduction in the prevalence of these lesions.5961 Recently, for
instance, Santakke et al.60 and Gaurav et al.61 reported a LGE
prevalence of 2.4% and 13.6%, respectively. In individuals not
undergoing HAART, the incidence of these lesions remained
high.
Although the association of LGE and NPD with HIV
infection is well established, the effect of HIV infection on
the progression of CP is not yet clear. A study performed before
the introduction of HAART verified that HIV-infected patients
greater than 35 years of age with CD4+ T lymphocyte levels
<200 cells/mm3 presented an accelerated progression of
previously existing CP.11 Reports on the prevalence of CP in
HIV-infected patients have also shown a wide variation of
results, mainly due to the difference in prevalence of
periodontal disease among the investigated populations and
the lack of a consistent definition for periodontal disease in
these studies.22,40 Due to these methodological problems it has
been difficult to determine the true prevalence of CP in
patients with moderate to advanced HIV-infection.
5. Immunological aspects of periodontal
disease in HIV-infected patients
It is well established that the development of periodontal
disease depends on the interplay between the resident
 archives of oral biology 58 (2013) 13851396
microbiota of the dental biofilm and the host response. The
initial response to bacterial infection is an inflammatory
reaction that activates the innate immune system.62,63 The
amplification of this localized response leads to the release of
various cytokines and other mediators with the spread of
inflammation through the gingival tissue.62,63 This entire
process occurs initially due to the colonization and invasion of
tissue by periodontal pathogens, which induce the host to
make use of a variety of defense mechanisms with the aim of
restoring the dynamic balance with the resident oral micro-
biota. The result of this pathogenhost interplay is the
activation of a sequence of host immune mechanisms that
may lead to periodontal tissue damage. This damage is the
result of a difficulty in keeping the inflammatory process
located at the gingival tissue, allowing the response to be
extended up to the subjacent alveolar bone. In other words,
most tissue damage is caused by the host response to infection,
leading to the destruction of the tooth support tissue. However,
it has been suggested that non HIV-infected patients with
periodontitis may have a monocyte hyperinflammatory re-
sponse to the periodontal pathogens lippolysaccharide
(LPS).64,65 In HIV-infected patients, the aetiology of periodontal
disease is not yet clear, particularly in the case of CP.
Prostaglandin plays an important role as an inflammatory
mediator in mucosal inflammation and host response, as well
as in performing an important molecular mechanism in the
pathogenesis of periodontal disease. Increased levels of this
mediator in gingival fluid can represent an important
biochemical predictor for the future progression of periodon-
tal disease in patients with CP.66 Hessle et al.67 demonstrated
that Gram-negative bacteria induce an intense production of
prostaglandin E2 (PGE2) in humans. This hyperactive response
of monocytes is even more important in immunosuppressed
patients and may contribute to the high levels of inflammatory
mediators such as interleukin 8 (IL8) and tumour necrosis
factor-a (TNF-a).68 AIDS patients present high levels of
circulating PGE2 and it appears that this suppresses the
specific antigen response of both lymphocytes Th1 and Th2.69
There is little information about the role of prostaglandins in
the aetiology of periodontitis in HIV-infected patients.
Recently, a longitudinal study showed that the presence of
high levels of PGE2 in subgingival sites can be a risk-factor for
the progression of pre-existing periodontitis in HIV-infected
patients. In this study there was a strong association between
PGE2 and probing depth and clinical attachment levels, both at
the baseline and six months later.70
In moderate conventional gingivitis there is a predomi-
nance of T lymphocytes, whereas in the destructive stage
there is a predominance of B lymphocytes. T cells are involved
in B-polyclonal cell modulation and in the activation and
release of lymphokines such as interleukins, which play a role
in the mediation of cellular migration, chemotaxis, growth
and differentiation.33 Immunohistochemical examination,
aimed at evaluating the types of cells found in biopsy samples
of HIV-infected patients with LGE and non HIV-infected
patients with conventional gingivitis, showed a greater
number of polymorphonuclear leukocytes (PMNs) and plas-
matic IgG-positive cells in the lesions of LGE and a greater
number of T lymphocytes and macrophages in conventional
gingivitis.33
1389
Investigations show evidence that levels of CD4+ T/CD8+ T
lymphocytes are reduced in the gingival tissue of patients with
chronic periodontitis when compared with their own periph-
eral blood or with the gingival tissue of healthy patients.71.72
These data suggest that periodontal disease is associated with
immunoregulation and CD4+ T lymphocytes. Steidley et al.71
reported a total lack of T lymphocytes in the gingival lamina
propria of biopsies from HIV-infected patients. Odden et al.72
evaluated gingival tissue from seropositive and seronegative
HIV individuals by imunohistochemical techniques and
identified CD4+ T and CD8+ T lymphocytes in the connective
tissue of seropositive individuals, however the number of
CD4+ T lymphocytes was decreased. Furthermore, the count of
CD8+ T lymphocytes was increased and the ratio of CD4+ T/
CD8+ T lymphocytes was decreased when compared to the
biopsies collected from seronegative individuals. Likewise, it
was shown that HIV-infected patients with periodontitis had
lower levels of Langerhans cells (LC) in the oral gingival
epithelium than non HIV-infected subjects.73 Segundo et al.74
reported contrasting results with higher counts of LCs in HIV-
infected individuals with moderate CP undergoing HAART
when compared to non HIV-infected individuals. The differ-
ence in results between studies may be because all HIV-
infected individuals in the study performed by Segundo et al.74
were undergoing HAART. Regarding mast cells in gingival
tissue, it has not been observed significant difference between
HIV-infected individuals undergoing HAART and non HIV-
infected individuals.75
For Lamster et al.76 the progression of periodontal disease
in HIV infection is dependent on the hosts immunological
ability as well as the inflammatory local response of the typical
and atypical subgingival microorganisms. The occurrence of
more complicated forms of periodontal destruction (NUP and
NS) in HIV-infected individuals seems to be associated with a
more pronounced immunodeficiency. It is likely that the
disseminated use of antibiotics, antifungal and antiretroviral
drugs used in the treatment of HIV-infection has an important
impact on the development of these lesions.
6. Periodontal microbiota in HIV-infected
patients
Several papers have studied the periodontal microbiota of
HIV-infected patients,17,20,32,38,7787 however these investiga-
tions encountered great difficulties in establishing the
periodontal microbiota profile of this population. For example,
some researchers78,79 included different forms of periodonti-
tis, such as CP, aggressive periodontitis (AP), NPD, in the same
microbiological analysis, resulting in conflicting data. Regard-
ing HIV-infected patients with chronic periodontitis, studies
have reported completely distinct results. In some investiga-
tions, the results indicated that the subgingival microbiota of
HIV-infected and non HIV-infected individuals have a similar
composition.82,85 Other studies detected a greater prevalence
of periodontal pathogens such as A. actinomycetemcomitans,
Fusobacterium nucleatum, P. gingivalis, Prevotella intermedia, T.
forsythia, and T. denticola, as well as a combination of these
species in HIV-infected patients compared to non HIV-
infected individual.38,83,84,86
1390 archives of oral biology 58 (2013) 13851396
Recent studies have demonstrated the important role of P.
gingivalis for the increase of invasion and HIV-1 infection in
oral epithelial cells in vitro,88,89 as well as inducing the re-
activation of HIV-1 which is found latent and integrated into
genomic DNA of infected cells of hosts. In fact re-activation
can be triggered by several species of oral bacteria and Candida
albicans or their components in dendritic cells and epithelial
cells.90 The bacterial species P. gingivalis can induce the
reactivation of HIV-1, which is found latent as provirus in
genomic host cells, through chromatin modification by butyric
acid a metabolite produced by P. gingivalis. This process
occurs by the biochemical modification of nucleosomal
histone proteins (by acetylation or deacetylation) through
the transcriptional activity of integrated HIV proviruses. These
results suggest that periodontal disease can actuate as a risk
factor for the reactivation of HIV-1 in HIV-infected individuals
and contribute to the dissemination of the virus.91,92
HIV-1 uses some chemokine receptors such as CCR5 and
CXCR4 to invade the host cells. In the presence of P. gingivalis,
the oral keratinocyte may present an increased expression of
oral chemokine receptors, mainly CCR5 through two mecha-
nisms. One mechanism occurs through the action of two types
of gingipains (the arginine-gingipains or Rgp and the lysine-
gingipain or Kgp).88,89 A relevant virulence factor of P. gingivalis
(which functions like cysteine proteinases) cleaves the
extracellular domain of the protease-activated receptors
(PARs), activating them and modulating the cytokine response
by the increase of the chemokine receptor expression. The
other mechanism occurs by LPS (an endotoxin of Gram-
negative bacteria) binding to the Toll-like receptor-4 (TLR-4) in
the cellular membrane of keratinocytes, activating it and
generating an increase in chemokine receptor expression. The
activation of these receptors is related to an increase in gene
expression involved in the inflammatory response, such as
that responsible for the synthesis of cytokines and chemo-
kines.88,89
In general, microorganisms not usually found in the
subgingival microbiota are considered opportunists since
they manifest under conditions of immunosuppression.
These species include Staphylococcus epidermidis and C. albi-
cans,72,77,93 some enterococcus species, such as E. faecalis,
some species of Clostridia, such as Clostridium clostridiiforme
and Clostridium difficile. The latter is often related with
pseudomembanous colitis, and Mycoplasma salivarium.20,77,81
However the role of these microrganisms in the pathogenesis
of destructive chronic periodontal disease in HIV-infected
patients is unknown. E. faecalis is significantly more prevalent
in the subgingival microbiota of HIV-infected patients with
reduced levels of CD4+ T lymphocytes (<200 cells/mm3),
suggesting that immunodeficiency can provide appropriate
conditions for the colonization and growth of opportunistic
pathogenic species uncommon in the oral mucosa.20
Candida species may actuate as opportunist microorgan-
isms without playing a direct role in the pathogenesis of
periodontal clinical attachment loss in HIV-infected patients,
however its presence may be related with immunological
deficiency inside the periodontal pocket. These yeasts could
potentially play a role in the pathogenesis of periodontal
disease by causing damage to junctional and crevicular
epithelium and thus the invasion of bacteria and fungi in
subjacent gingival connective tissue. It has also been shown
that species of Candida can induce a significant response of
proinflammatory cytokines,94 which could contribute to an
increase of periodontal clinical attachment loss observed in
HIV-infected patients. C. albicans95,96 and Candida dubliniensis32
have been the most frequently detected species in subgingival
sites of these individuals.
A recent study17 reported that non HIV-infected individuals
presented with higher levels and a greater mean of prevalence
of oral microorganisms when compared with HIV-infected
patients undergoing HAART, independent of periodontal
status (Figs. 8 and 9). However in the same study, the data
showed that Acinetobacter baumannii, E. faecalis and Pseudomo-
nas aeruginosa, opportunist microorganisms involved in
hospital infection, were more prevalent in infected patients
than in non HIV-infected patients, independent of periodontal
status (Figs. 8 and 9). Interestingly, it was reported in this study
that HIV-infected patients with chronic periodontitis had
colonization by fewer bacterial species, including several
periodontal pathogens than non HIV-infected patients. Others
researchers did not find significant differences between HIV-
infected and non-infected patients regarding periodontal
pathogens.82,85,97 Cross and Smith38 reported that periodontal
pathogens were detected more often in HIV-infected patients
with chronic periodontitis. The differences between these
studies can be explained by the application of distinct
methods for detection and identification of microorganisms,
the quantity of biofilm samples analyzed, the kind of
periodontal infection investigated, as well as the ethnic,
geographic and environmental features of the target popula-
tion.98,99
Most of the studies mentioned in the scientific literature
evaluated few bacterial species in a limited quantity of
subgingival biofilm samples. The more frequently used
methods included culture,82,85,94 PCR,86,97 DNA probe38,83
and dark field microscopy.82 In any investigated population,
the decrease in samples and species evaluated can result in a
sub or super estimation of specific microorganisms in the
microbiota associated with periodontal disease. Haffajee and
Socransky,100 for instance, showed that, on average, a species
was not detected in 68% of the positive subjects if only the
upper right first molar was sampled; 60% of subjects if the
deepest pocket was sampled, and 25% of subjects if the four
deepest pockets were sampled. This data indicates that
analysis of multiple biofilm samples is necessary to reduce
the probability of false negative results. Thus, the evaluation
of complex microbial ecosystems, such as the periodontal
microbiota, demands the application of techniques that allow
the detection of a number of bacterial species in large
quantities of biofilm samples.99,100
Another aspect to be considered in investigations of the
periodontal microbiota of HIV-infected patients is the immu-
nological status of these individuals. The levels of CD4+ T
lymphocytes and the viral load have been used as immuno-
logical markers in this population.21 It is expected that HIV-
infected patients, seriously immunodeficient and with peri-
odontitis should be more likely to be infected by periodontal
pathogens. Goncalves et al.17 reported that in spite of the low
levels of CD4+ T lymphocytes and the high viral load in a
Brazilian HIV-infected group, they did not harbour larger
 archives of oral biology 58 (2013) 13851396 1391

Mean % of samples Mean counts (X105 cells)

0 20 40 60 80 0 2 4 6 8
A.actinomycetemcomitans a A.actinomycetemcomitans a
A.actinomycetemcomitans b * A.actinomycetemcomitans b
A. gerencseriae A. gerencseriae
A. israelli *A. israelli
A. odontolyticus *A. odontolyticus
*A. naeslundii I *A. naeslundii I
A. oris A. oris
T. forsythia T. forsythia
C. rectus *C. rectus

C. ochracea * C. ochracea
*C. gingivalis
C. gingivalis
C. sputigena
C. sputigena
C. showae
C. showae
E. nodatum
E. nodatum
*E. corrodens
*E. corrodens
E. saburreum
E. saburreum
F. periodonticum
*F. periodonticum
F. nuc. polymorphum
F. nuc. polymorphum
F. nuc.vincentii
F. nuc.vincentii F. nuc. nucleatum
F. nuc. nucleatum G. morbillorum
G. morbillorum *L. buccalis
*L. buccalis N. mucosa
N. mucosa P. intermedia
P. intermedia P. acnes I + II
*P. acnes I + II P. micra
P. micra P. gingivalis
P. gingivalis P. melaninogenica
P. melaninogenica P. nigrescens
P. nigrescens S. constellatus
S. constellatus S. intermedius

*S. intermedius S. anginosus

S. gordonii
S. anginosus
S. oralis
S. gordonii
S. sanguinis
S. oralis
S. mitis
S. sanguinis
S. noxia
S. mitis
*T. denticola
S. noxia
V. parvula
*T. denticola
H. pylori
V. parvula
A. baumannii
H. pylori E. coli
A. baumannii *E. faecalis
E. coli P. aeruginosa
*E. faecalis S. aureus
P. aeruginosa A.actinomycetemcomitans c
S. aureus D. pneumosintes
A.actinomycetemcomitans c
*D. pneumosintes Fig. 7 Microbial profiles of the mean counts (T105 cells) of
47 oral species examined in subgingival biofilm samples
Fig. 6 Microbial profile of the mean frequency of 47 oral from 6 HIV-infected individuals. *Eleven bacterial species
species examined in subgingival biofilm samples from 6 had mean counts >105 cells.103
HIV-infected individuals. *Eight bacterial species were This figure is being reproduced with permission from the
detected in I60% of the samples.103 Quintessence International.
This figure is being reproduced with permission from the
Quintessence International.

periodontal disease have been reported.17,20,32,38,7786 Howev-

proportions of periodontal pathogens compared to the non er, very few studies have examined the microbiota associated
HIV-infected group. with NPD in HIV-infected individuals.101,102 In these studies,
A large number of studies describing the periodontal several microorganisms have been found, such as F. alocis, P.
microbiota of HIV-infected individuals with or without endodontalis, F. nucleatum ss. Vincenti, Desulfovibrio clone BB161
1392 archives of oral biology 58 (2013) 13851396
and Dialister pneumosintes101 as well as high levels of
spirochetes, yeast and herpes-like viruses.102 This data
indicates that the subgingival biofilm associated with NPD
may present a very complex and diverse composition.
Recently a descriptive study assessed subgingival biofilm
samples from six Brazilian adults with NPD for the presence of
47 species by chequerboard DNADNA hybridization.103 High
levels of putative periodontal pathogens such as A. actinomy-
cetemcomitans and T. denticola were detected frequently in the
biofilm associated with these lesions. Other species, not
commonly considered as periodontal pathogens, particularly
E. faecalis and D. pneumosintes were also observed at high levels
in these lesions (Figs. 6 and 7).
The establishment of HAART may have provided a
protector effect, keeping the pathogenic subgingival micro-
biota of these patients under control, even in conditions of
severe immunodeficiency. In fact, microbiological studies of
HIV-infected patients should be separated into before and
after the introduction of HAART. Published research before
the introduction of HAART showed a greater prevalence of
periodontitis and periodontal pathogens in HIV-infected
patients when compared to seronegative individuals.38 The
introduction of HAART provided a significant improvement in
the quality of life of these patients.22 Antiretroviral therapy
may also have improved the clinical periodontal features of
HIV-infected individuals leading to a reduction in the
incidence and prevalence of periodontitis as well as the
presence of periodontal pathogens in the subgingival micro-
biota of these individuals.15,82,83,85,86,97 Evidence shows that
this class of antiretrovirals may also inhibit proteinases and
others microorganisms, such as Candida species.21,104
The presence of HIV in subgingival sites may also play an
important role in the pathogenesis of periodontal disease in
seropositive patients.22 The infection of periodontal tissue by
HIV would act as a co-factor for the development of
destructive periodontal disease through a direct lytic effect
on cells of the gingival epithelium.105,106 The presence of
100
Yellow complex
Blue complex.
80
Purple complex
Green complex
60
Mean %
40
20
Fig. 8 Microbial profiles of the mean frequency of 33 oral species examined in subgingival biofilm samples from 72 HIV-
seropositive and 100 HIV-seronegative individuals. The percentage of sites colonized by each species was computed for
each patient and averaged across subjects within the groups. The species were ordered according to the microbial
complexes. The MannWhitney test was used to determine the significance of differences between groups. Analysis of
covariance (GLM test) was performed using age and gender as covariates. *P < 0.05, MannWhitney test, and yP < 0.05, GLM
test, using age and smoking as covariates; adjusted for multiple comparisons.17
This figure is being reproduced with permission from the American Academy of Periodontology.
retroviral particles has been described in lesions of oral and
esophageal ulcerations in the acute stage of HIV infection,
suggesting a direct etiological role of the virus in certain
pathological conditions.107 Others viruses, especially herpes
viruses, such as cytomegalovirus, EpsteinBarr virus and
herpes simplex, may also play an important role in periodon-
tal pathogenesis of HIV-infected individuals.108114 These
viruses are found at more increased levels in subgingival
sites of HIV-infected patients than in non-infected
patients.110,115 In spite of this, it is not possible for us to
determine the true role of herpes viruses in the aetiology of
periodontal disease in these individuals. The presence of
increased levels of these viruses in periodontal tissues could
provide the required growth conditions for other periodontal
pathogens as well as opportunist microorganisms through the
suppression of host defense mechanisms and through the
increase of secretion of proinflammatory cytokines as IL-1 and
TNF-a.111 However, recent studies in vitro showed that
cytomegalovirus and EpsteinBarr virus can inhibit macro-
phage activity in phagocytes and produce TNF-a induced by
periodontal pathogens such as A. actinomycetemcomitans, P.
gingivalis and F. nucleatum.112 In addition, it has been verified
that co-infection of the subgingival microbiota by different
herpes viruses can increase the levels of periodontal patho-
gens in subgingival sites.106,115 Therefore tissue invasion by
virus, yeast and others opportunist microorganisms could
explain, in part, the standard of periodontal destruction in HIV
infection.22
7. Final comments
HIV infection is a relatively new disease, reported approxi-
mately three decades ago. This pandemic virus has been
continuously studied in order to deepen knowledge about it.
The understanding of all aspects of HIV infection is critical in
assessing its impact on other diseases, such as periodontal
Orange complex
Red complex
HIV-seronegative
HIV-seropositive
Other species
 archives of oral biology 58 (2013) 13851396 1393

10

Orange complex

Red complex
Yellow complex

Other species
Green complex
Blue complex.

Purple complex
Mean counts (X 10 5 cells)
HIV-seronegative
8
HIV-seropositive

Fig. 9 Microbial profiles of the mean counts (T105) of 33 oral species examined in subgingival biofilm samples from 72 HIV-
seropositive and 100 HIV-seronegative individuals. The percentage of sites colonized by each species was computed for
each patient and averaged across subjects within the groups. The species were ordered according to the microbial
complexes. The MannWhitney test was used to determine the significance of differences between groups. Analysis of
covariance (GLM test) was performed using age and gender as covariates. *P < 0.05, MannWhitney test, and yP < 0.05, GLM
test, using age and smoking as covariates; adjusted for multiple comparisons.17
This figure is being reproduced with permission from the American Academy of Periodontology.

diseases. In fact, it is impossible to establish a treatment plan 2. UNAIDS. Chronic care of HIV and non-communicable diseases:
for other diseases affecting HIV-infected individuals without how to leverage the HIV experience. 2011.
3. Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK.
assessing their immunological condition and use of antiretro-
Guidelines for using antiretroviral agents among HIV-
viral therapy. The true impact of HIV-infection on the clinical, infected adults and adolescents. Annals of Internal Medicine
immunological and microbiological aspects of periodontal 2002;137:381433.
disease is not entirely clear. Several studies regarding the co- 4. UNAIDS. Report on the global HIV/AIDS epidemic. 2008.
existence of HIV and periodontal disease allow a better 5. Palella Jr FJ, Delaney KM, Moorman AC, Loveless MO,
understanding of both diseases, and contribute to the Fuhrer J, Satten GA, et al. Declining morbidity and
mortality among patients with advanced human
knowledge of periodontists and general dental practitioners,
immunodeficiency virus infection. New England Journal of
leading to proper periodontal treatment.
Medicine 1998;13:85360.
6. Schmidt-Westhausen AM, Priepke F, Bergman FJ, Reichart
PA. Decline in the rate of oral opportunistic infections
Funding following introduction of highly active retroviral therapy.
Journal of Oral Pathology and Medicine 2000;29:33641.
None. 7. Greenspan JS, Greenspan D. The epidemiology of the oral
lesions of HIV infection in the developed world. Oral
Diseases 2002;8(Suppl. 2):349.
8. Ramirez-Amador V, Esquivel-Pedraza L, Sierra-Madero J,
Competing interests
Anaya-Saavedra G, Gonzalez-Ramirez I, Ponce-de-Leon S.
The changing clinical spectrum of human
None declared. immunodeficiency virus (HIV)-related oral lesions in 1,000
consecutive patients: a 12 year study in a referral centre in
Mexico. Medicine 2003;82:3950.
Ethical approval 9. Bascones A, Serrano C, Campo J. Oral manifestations of HIV
infection. Medicina Clinica 2003;120:42634.
10. Robinson PG, Adegboye A, Rowland RW, Yeung S, Johnson
Not required. N. Periodontal disease and HIV infection. Oral Diseases
2002;8(Suppl. 2):14450.
references 11. Barr C, Lopez MR, Rua-Dobles A. Periodontal changes by
HIV serostatus in a cohort of homosexual and bisexual
men. Journal of Periodontology 1992;19:794801.
12. Maticic M, Poljak M, Kramar B, Tomazic J, Vidmar L,
1. Horstmann E, Brown J, Islam F, Buck J, Agins B. Retaining Zakotnik B, et al. Proviral HIV-1 DNA in gingival crevicular
HIV-infected patients in care: where are we? Where do we fluid of HIV 1-infected patients in various stages of HIV
go from here? Clinical Infectious Diseases 2010;50: disease. Journal of Dental Research 2000;79:
75261. 1496501.
1394 archives of oral biology 58 (2013) 13851396
13. McKaig RG, Patton LL, Thomas JC, Strauss RP, Slade GD,
Beck JD. Factors associated with periodontitis in an HIV-
infected southeast USA study. Oral Diseases 2000;6:
15865.
14. Hofer D, Hammerle CH, Grassi M, Lang NP. Long-term
results of supportive periodontal therapy (SPT) in HIV-
seropositive and HIV-seronegative patients. Journal of
Clinical Periodontology 2002;29:6307.
15. Goncalves LS, Ferreira SM, Silva Jr A, Villoria GE, Costinha
LH, Colombo AP. Association of T CD4 lymphocyte levels
and chronic periodontitis in HIV-infected Brazilian
patients undergoing highly active anti-retroviral therapy.
Clinical results. Journal of Periodontology 2005;76:90613.
16. Alves M, Mulligan R, Passaro D, Gawell S, Navazesh M,
Phelan J, et al. Longitudinal evaluation of loss of
attachment in HIV-infected women compared to HIV-
uninfected women. Journal of Periodontology 2006;77:7739.
17. Goncalves LS, Ferreira SM, Souza CO, Souto R, Colombo AP.
Clinical and microbiological profiles of human
immunodeficiency virus (HIV)-seropositive Brazilians
undergoing highly active antiretroviral therapy and HIV-
seronegative Brazilians with chronic periodontitis. Journal
of Periodontology 2007;78:8796.
18. Aichelmann-Reidy ME, Wrigley DL, Gunsolley JC. HIV
infection and bone loss due to periodontal disease. Journal
of Periodontology 2010;81:87784.
19. Fricke U, Geurtsen W, Staufenbiel I, Rahman A. Periodontal
status of HIV-infected patients undergoing antiretroviral
therapy compared to HIV-therapy nave patients: a case
control study. European Journal of Medical Research
2012;17:2.
20. Goncalves LS, Ferreira SM, Silva Jr A, Villoria GE, Costinha
LH, Souto R, et al. Association of TCD4 lymphocyte levels
and subgingival microbiota of chronic periodontitis in HIV-
infected Brazilian under HAART. Oral Surgery Oral Medicine
Oral Pathology Oral Radiology and Endodontics 2004;97:
196203.
21. Munro CA, Hube B. Anti-fungal therapy at the HAART of
viral therapy. Trends in Microbiology 2002;10:1737.
22. Ryder MI. An update on HIV and periodontal disease.
Journal of Periodontology 2002;73:10718.
23. Yin MT, Dobkin JF, Grbic JT. Epidemiology, pathogenesis,
and management of human immunodeficiency virus
infection in patients with periodontal disease.
Periodontology 2000 2007;44:5581.
24. Armitage GC. Development of a classification system for
periodontal diseases and conditions. Annals of
Periodontology 1999;4:16.
25. Sanz M, van Winkelhoff AJ. Working group 1 of seventh
European Workshop on Periodontology. Periodontal
infections: understanding the complexityconsensus of
the seventh European workshop on periodontology. Journal
of Clinical Periodontology 2011;38(Suppl. 11):36.
26. Offenbacher S. Periodontal diseases: pathogenesis. Annals
of Periodontology 1996;1:82178.
27. Page RC, Kornman KS. The pathogenesis of human
periodontitis: an introduction. Periodontology 2000
1997;14:911.
28. Winkler JR, Murray PA. Periodontal disease. A potential
intraoral expression of AIDS may be rapidly progressive
periodontitis. CDA Journal 1987;15:204.
29. Holmstrup P. Nonplaque-induced gingival lesions. Annals
of Periodontology 1999;4:2031.
30. Reznik DA. Oral manifestations of HIV disease. Topics in
HIV Medicine 2006;13:1438.
31. Grbic JT, Mitchell-Lewis DA, Fine JB, Phelan JA, Bucklan RS,
Zambon JJ, et al. The relationship of candidiasis to linear
gingival erythema in HIV-infected homosexual men and
parenteral drug users. Journal of Periodontology 1995;66:307.
32. Jabra-Rizk MA, Ferreira SM, Sabet M, Falkler WA, Merz WG,
Meiller TF. Recovery of Candida dubliniensis and other yeast
from human immunodeficiency virus associated
periodontal lesions. Journal of Clinical Microbiology
2001;39:45202.
33. Gomez RS, da Costa JE, Loyola AM, de Araujo NS, de Araujo
VC. Immunohistochemical study of linear gingival
erythema from HIV-positive patients. Journal of Periodontal
Research 1995;30:3559.
34. Lamster IB, Grbic JT, Fine J, BucklanR. Mitchell-Lewis D,
Phelan J, et al. A critical review of periodontal disease as a
manifestation of HIV infection. In: Greenspan JS, Greenspan
D, editors. Oral Manifestations of HIV Infection. Chicago:
Quintessence Publishing Company; 1995. p. 24756.
35. Patton LL. Sensitivity, specificity, and positive predictive
value of oral opportunistic infections in adults with HIV/
AIDS as markers of immune suppression and viral burden.
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and
Endodontics 2000;90:1828.
36. Novak MJ. Necrotizing ulcerative periodontitis. Annals of
Periodontology 1999;4:748.
37. Lang N, Soskolne WA, Greenstein G, Chrocan D, Corbet E,
Meng HX, et al. Consensus report: necrotizing periodontal
diseases. Annals of Periodontology 1999;4:78.
38. Cross DL, Smith GLF. Comparison of periodontal disease in
HIV seropositive subjects and controls. (II) Microbiology,
immunology and predictors of disease progression. Journal
of Clinical Periodontology 1995;22:56977.
39. Glick M, Muzyka BC, Salkin LM, Lurie D. Necrotizing
ulcerative periodontitis: a marker for immune
deterioration and a predictor for the diagnosis of AIDS.
Journal of Periodontology 1994;65:3937.
40. Lamster IB, Grbic JT, Bucklan RS, Mitchel LD, Reynolds HS,
Zambon JJ. Epidemiology and diagnosis of HIV associated
periodontal diseases. Oral Diseases 1997;3(suppl 1):1418.
41. Epstein JB, Leziy S, Ransier A. Periodontal pocketing in HIV
associated periodontitis. Special Care in Dentistry 1993;3:236
40.
42. Shangase L, Feller L, Blignaut E. Necrotizing ulcerative
gingivitis/periodontitis as indicators of HIV-infection. Small
Arms Defense Journal 2004;59:1058.
43. Glick M, Muzyka BC, Luried D, Salkin LM. Oral
Manifestations associated with HIV related disease as
markers for immune suppression and AIDS. Oral Surgery
Oral Medicine Oral Pathology 1994;77:3449.
44. Wood NH, Blignaut E, Lemmer J, Meyerov R, Feller L.
Necrotizing periodontal diseases in a semirural district of
South Africa. AIDS Research and Treatment 2011. http://
dx.doi.org/10.1155/2011/638584. [Epub 2011 Jun 21].
45. National Program for STD and AIDS/Bulletin November
2009. Brasilia, DF: Brazilian Ministry of Health (in
Portuguese).
46. Shelburne 3rd SA, Hamill RJ, Rodriguez-Barradas MC,
Greenberg SB, Atmar RL, Musher DW, et al. Immune
reconstitution inflammatory syndrome: emergence of a
unique syndrome during highly active antiretroviral
therapy. Medicine 2002;81:21327.
47. Singh N, Perfect JR. Immune reconstitution syndrome
associated with opportunistic mycoses. Lancet Infectious
Diseases 2007;7:395401.
48. Yeung SC, Stewart GJ, Cooper DA, Sindhusake D.
Progression of periodontal disease in HIV seropositive
patients. Journal of Periodontology 1993;64:6517.
49. Tomar SL, Swango A, Kleinman DV, Burt BA. Loss of
periodontal attachment in HIV-seropositive military
personnel. Journal of Periodontology 1995;66:4218.
50. Robinson PG, Sheiham A, Challacombe SJ, Zakrzewska JM.
The periodontal health of homosexual men with HIV
infection: a controlled study. Oral Diseases 1996;2:4552.
 archives of oral biology 58 (2013) 13851396
51. Ndiaye CF, Critchlow CW, Leggott PJ, Kiviat NB, Ndoye I,
Robertson PB, et al. Periodontal status of HIV-1 and HIV-2
seropositive and HIV seronegative female commercial sex
workers in Senegal. Journal of Periodontology 1997;68:82731.
52. Swango PA, Kleinman DV, Konzelman JL. HIV and
periodontal health. A study of military personnel with HIV.
Journal of the American Dental Association 1991;122:4954.
53. Winkler JR, Grassi M, Murray PA. Clinical description and
etiology of HIV associated periodontal diseases. In:
Robertson PB, Greenspan JS, editors. Perspectives on oral
manifestations of AIDS. Littleton, CO: PSG Publishing Co. Inc.;
1988. p. 4970.
54. Silva Jr A, Ferreira SMS, Perez MA, Albuquerque EB, Camilo
RS, Torres SR. Experience on 584 HIV + patients of a dental
referal center. Tenth international conference on AIDS
international conference on STD. 1994.
55. Bertazzoli R, Lourenco C. Oral Manifestation. Oral
manifestations of HIV infection in Campinas city. Tenth
international conference on AIDSinternational conference on
STD. 1994.
56. Ferreira S, Noce C, Junior AS, Goncalves L, Torres S, Meeks
V, et al. Prevalence of oral manifestations of HIV infection
in Rio de Janeiro, Brazil from 1988 to 2004. AIDS Patient Care
STDS 2007;21:72431.
57. Ceballos-Salobrena A, Gaitan-Cepeda LA, Ceballos-Garcia
L, Lezama-Del Valle D. Oral lesions in HIV/AIDS patients
undergoing highly active antiretroviral treatment
including protease inhibitors: a new face of oral AIDS? Aids
Patient Care and STDS 2000;14:62735.
58. Nittayananta W, Talungchit S, Jaruratanasirikul S,
Silpapojakul K, Chayakul P, Nilmanat A, et al. Effects of
long-term use of HAART on oral health status of HIV-
infected subjects. Journal of Oral Pathology and Medicine
2010;39:397406.
59. Patton LL, Phelan JA, Ramos-Gomez FJ, Nittayananta W,
Shiboski CH, Mbuguye TL. Prevalence and classification of
HIV-associated oral lesions. Oral Diseases 2002;8(Suppl.
2):98109.
60. Sontakke SA, Umarji HR, Karjodkar F. Comparison of oral
manifestations with CD4 count in HIV-infected patients.
Indian Journal of Dental Research 2011;22:732.
61. Gaurav S, Keerthilatha PM, Archna N. Prevalence of oral
manifestations and their association with CD4/CD8 ratio
and HIV viral load in South India. International Journal of
Dentistry 2011;2011:964278. http://dx.doi.org/10.1155/2011/
964278. [Epub 2011 Oct 20].
62. Hans M, Hans VM. Toll-like receptors and their dual role in
periodontitis: a review. Journal of Oral Science 2011;53:
26371.
63. Scott DA, Krauss J. Neutrophils in periodontal
inflammation. Frontiers of Oral Biology 2012;15:5683.
64. Alpagot T, Duzgunes N, Wolff LF, Lee A. Risk factors for
periodontitis in HIV+ patients. Journal of Periodontal Research
2004;39:14957.
65. Alpagot T, Suzara V, Bhattacharyya M. The associations
between gingival crevice fluid matrix metalloproteinase-9,
tissue inhibitor of metalloproteinase-1 and periodontitis in
human immunodeficiency virus-positive patients. Journal
of Periodontal Research 2006;41:4917.
66. Offenbacher S, Odle BM, Van Dyke TE. The use of crevicular
fluid prostaglandin E2 levels as a predictor of periodontal
attachment loss. Journal of Periodontal Research 1986;21:
10112.
67. Hessle CC, Andersson B, Wold AE. Gram-negative, but not
Gram-positive, bacteria elicit strong PGE2 production in
human monocytes. Inflammation 2003;27:32932.
68. Dunne DW, Shaw A, Bockenstedt LK, Allore HG, Chen S,
Malawista SE, et al. Increased TLR4 expression and
downstream cytokine production in immunosuppressed
1395
adults compared to non-immunosuppressed adults. PLoS
ONE 2010;5(6):e11343.
69. Foley P, Kazazi F, Biti R, Sorrell TC, Cunningham AL. HIV
infection of monocytes inhibits the T-lymphocyte
proliferative response to recall antigens, via production of
eicosanoids. Immunology 1992;75:3917.
70. Alpagot T, Remien J, Bhattacharyya M, Konopka K,
Lundergan W, Duzgunes N. Longitudinal evaluation of
prostaglandin E2 (PGE2) and periodontal status in HIV+
patients. Archives of Oral Biology 2007;52:11028.
71. Steidley KE, Thompson SH, McQuade MJ, Strong SL,
Scheidt MJ, Van Dyke TE. A comparison of T4:T8
lymphocyte ratio in the periodontal lesion of healthy and
HIV-positive patients. Journal of Periodontology
1992;63:7536.
72. Odden K, Schenck K, Koppang H, Hurlen B. Candidal
infection of the gingiva in HIV-infected persons. Journal of
Oral Pathology and Medicine 1994;23:17883.
73. Myint M, Yuan ZN, Schenck K. Reduced numbers of
Langerhans cells and increased HLA-DR expression in
Keratinocytes in the oral gingival epithelium of HIV-
infected patients with periodontitis. Journal of Clinical
Periodontology 2000;27:5139.
74. Segundo TK, Souto GR, Mesquita RA, Costa FO. Langerhans
cells in periodontal disease of HIV and HIV+ patients
undergoing highly active antiretroviral therapy. Brazilian
Oral Research 2011;25:25560.
75. Segundo TK, Souto GR, Costa FO, Mesquita RA. Mast cells in
the periodontal disease of non-HIV-infected and HIV-
infected individuals undergoing highly active antiretroviral
therapy. Journal of Periodontology 2012. [Epub ahead of print].
76. Lamster IB, Grbic JT, Mitchell-Lewis DA, Begg MD, Mitchell
A. New concepts regarding the pathogenesis of periodontal
disease in HIV infection. Annals of Periodontology 1998;3:
6275.
77. Zambon JJ, Reynolds HS, Genco RJ. Studies of the
subgingival microflora patients with acquired
immunodeficiency syndrome. Journal of Periodontology
1990;61:699704.
78. Murray PA, Winkler JR, Peros WJ, French CK, Lippke JA.
DNA probe detection of periodontal pathogens in HIV-
associated periodontal lesions. Oral Microbiology and
Immunology 1991;6:3440.
79. Lucht E, Heimdahl A, Nord CE. Periodontal disease in HIV-
infected patients in relation to lymphocyte subsets and
specific micro-organisms. Journal of Clinical Periodontology
1991;18:2526.
80. Rams TE, Andriolo Jr M, Feik D, Abel SN, McGivern TM,
Slots J. Microbiological study of HIV-related periodontitis.
Journal of Periodontology 1991;62:7481.
81. Moore LV, Moore WE, Riley C, Brooks CN, Burmeister JA,
Smibert RM. Periodontal microflora of HIV positive subjects
with gingivitis or adult periodontitis. Journal of
Periodontology 1993;64:4856.
82. Brady LJ, Walker C, Oxford GE, Stewart C, Magnusson I,
McArthur W. Oral diseases, mycology and periodontal
microbiology of HIV-1-infected women. Oral Microbiology
and Immunology 1996;11:37180.
83. Tenenbaum H, Elkaim R, Cuisinier F, Dahan M, Zamanian
P, Lang JM. Prevalence of six periodontal pathogens
detected by DNA probe method in HIV vs non-HIV
periodontitis. Oral Diseases 1997;3(Suppl. I):S1535.
84. Scully C, Porter SR, Mutlu S, Epstein JB, Glover S, Kumar N.
Periodontopathic bacteria in English HIV seropositive
persons. Aids Patient Care and STDS 1999;13:36974.
85. Tsang CSP, Samaranayake LP. Predominant cultivable
subgingival microbiota of health and HIV-infected ethnic
Chinese. Journal of Oral Pathology & Medicine 2001;109:
11726.
1396 archives of oral biology 58 (2013) 13851396
86. Patel M, Coogan M, Galpin JS. Periodontal pathogens in
subgingival plaque of HIV-positive subjects with chronic
periodontitis. Oral Microbiology and Immunology
2003;18:199201.
87. Goncalves LS, Souto R, Colombo AP. Detection of
Helicobacter pylori, Enterococcus faecalis, and Pseudomonas
aeruginosa in the subgingival biofilm of HIV-infected
subjects undergoing HAART with chronic periodontitis.
European Journal of Clinical Microbiology & Infectious
2009;28:133542.
88. Giacaman RA, Nobbs AH, Ross KF, Herzberg MC.
Porphyromonas gingivalis selectively up-regulates the HIV-
coreceptor CCR5 in oral keratinocytes. Journal of
Immunology 2007;179:254250.
89. Giacaman RA, Asrani AC, Gebhard KH, Dietrich EA,
Vacharaksa A, Ross KF, et al. Porphyromonas gingivalis
induces CCR5-dependent transfer of infectious HIV-1 from
oral keratinocytes to permissive cells. Retrovirology
2008;5:29.
90. Huang CB, Alimova YV, Strange S, Ebersole JL. Polybacterial
challenge enhances HIV reactivation in latently infected
macrophages and dendritic cells. Immunology
2011;132:4019.
91. Imai K, Ochiai K, Okamoto T. Reactivation of latent HIV-1
infection by the periodontopathic bacterium Porphyromonas
gingivalis involves histone modification. Journal of
Immunology 2009;182:368895.
92. Imai K, Ochiai K. Role of histone modification on
transcriptional regulation and HIV-1 gene expression:
possible mechanisms of periodontal diseases in AIDS
progression. Journal of Oral Science 2011;53:113.
93. Chattin BR, Ishihara K, Okuda K, Hirai Y, Ishikawa T.
Specific microbial colonizations in the periodontal sites of
HIV-infected subjects. Microbiology and Immunology
1999;43:84752.
94. Dongari-Bagtzoglou A, Fidel Jr PL. The host cytokine
responses and protective immunity in oropharyngeal
candidiasis. Journal of Dental Research 2005;84:96677.
95. Back-Brito GN, Mota AJ, Vasconcellos TC, Querido SM, Jorge
AO, Reis AS, et al. Frequency of Candida spp. in the oral
cavity of Brazilian HIV-positive patients and correlation
with CD4 cell counts and viral load. Mycopathologia
2009;167:817.
96. Junqueira JC, Vilela SF, Rossoni RD, Barbosa JO, Costa AC,
Rasteiro VM, et al. Oral colonization by yeasts in HIV-
positive patients in Brazil. Revista do Instituto de Medicina
Tropical de Sao Paulo 2012;54:1724.
97. Teanpaisan R, Douglas CW, Nittayananta W. Isolations and
genotyping of black-pigmented anaerobes from
periodontal sites of HIV-positive and non-infected subjects
in Thailand. Journal of Clinical Periodontology 2001;28:3118.
98. Loesche WJ, Lopatin DE, Stoll J, van Poperin N, Hujoel PP.
Comparison of various detection methods for
periodontopathic bacteria: can culture be considered the
primary reference standard? Journal of Clinical Microbiology
1992;30:41826.
99. Loos BG, Van Winkelhoff AJ, Dunford RG, Genco RJ, De
Graaff J, Dickinson DP, et al. A statistical approach to the
ecology of Porphyromonas gingivalis. Journal of Dental Research
1992;71:3538.
100. Haffajee AD, Socransky SS. Effect of sampling strategy on
the false-negative rate for detection of selected subgingival
species. Oral Microbiology and Immunology 1992;7:579.
101. Paster BJ, Russell MK, Alpagot T, Lee AM, Boches SK, Galvin
JL, et al. Bacterial diversity in necrotizing ulcerative
periodontitis in HIV-positive subjects. Annals of
Periodontology 2002;7:816.
102. Cobb CM, Ferguson BL, Keselyak NT, Holt LA, MacNeill SR,
Rapley JW. A TEM/SEM study of the microbial plaque
overlying the necrotic gingival papillae of HIV-seropositive,
necrotizing ulcerative periodontitis. Journal of Periodontal
Research 2003;38:14755.
103. Ramos MP, Ferreira SM, Silva-Boghossian CM, Souto R,
Colombo AP, Noce CW, et al. Necrotizing periodontal
diseases in HIV-infected Brazilian patients: a clinical and
microbiological descriptive study. Quintessence International
2012;43:7182.
104. Detels R, Tarwater P, Phair JP, Margolick J, Riddler SA,
Munoz A, Multicenter AIDS Cohort Study Multicenter AIDS
Cohort Study. Effectiveness of potent antiretroviral
therapy on the incidence opportunistic infection before
and AIDS diagnosis. AIDS 2001;15:34755.
105. Parra B, Slots J. Detection of human viruses in periodontal
pockets using polymerase chain reaction. Oral Microbiology
and Immunology 1996;5:28993.
106. Contreras A, Umeda M, Chen C, Bakker I, Morrison JL, Slots
J. Relationship between herpesviruses and adult
periodontitis and periodontopathic bacteria. Journal of
Periodontology 1999;70:47884.
107. Ficarra G. Oral ulcerations in patients with HIV infection:
etiology, diagnosis and management. In: Greenspan D,
Greenspan JS, editors. Oral Manifestation of HIV Infection.
Chicago: Quintessence Publishing Co Inc.; 1995. p. 20517.
108. Dodd CL, Winkler JR, Heinic GS, Daniels TE, Yee K,
Greenspan D. Cytomegalovirus infection presenting as
acute periodontal infection in a patient infected with the
human immunodeficiency virus. Journal of Clinical
Periodontology 1993;20:2825.
109. Contreras A, Slots J. Mammalian viruses in human
periodontitis. Oral Microbiology and Immunology
1996;11:3816.
110. Mardirossian A, Contreras A, Navazesh M, Nowzari H, Slots
J. Herpesviruses 6, 7 and 8 in HIV and non HIV-associated
periodontitis. Journal of Periodontal Research 2000;35:27884.
111. Slots J, Contreras A. Herpersviruses: a unifying causative
factor in periodontitis? Oral Microbiology and Immunology
2000;15:27780.
112. Lin Y-L, Li M. Human cytomegalovirus and EpsteinBarr virus
inhibit oral bacteria-induced macrophage activation and
phagocytosis. Oral Microbiology and Immunology 2009;24:2438.
113. Grande SR, Imbronito AV, Okuda OS, Pannuti CM, Nunes
FD, Lima LA. Relationship between herpesviruses and
periodontopathogens in patients with HIV and
periodontitis. Journal of Periodontology 2011;82:144252.
114. Contreras A, Mardirossian A, Slots J. Herpesviruses in HIV-
periodontitis. Journal of Clinical Periodontology 2001;28:96102.
115. Michalowicz BS, Ronderos M, Camara-Silva R, Contreras A,
Slots J. Human herpesviruses and Porphyromonas gingivalis
are associated with juvenile periodontitis. Journal of
Periodontology 2000;71:9818.