J Periodont Res 2000; 35: 3±16 Copyright # Munksgaard 2000

Printed in UK. All rights reserved

JOURNAL OF
PERIODONTAL RESEARCH
ISSN 0022-3484

Short review

Herpesviruses in human
Adolfo Contreras1,2, Jùrgen Slots1
1
Department of Periodontology, School of
Dentistry, University of Southern California,

periodontal disease
Los Angeles, CA, USA, 2Department of
Periodontology, School of Dentistry, University
of Valle, Cali, Colombia

Contreras A, Slots J: Herpesviruses in human periodontal disease. J Periodont Res

2000; 35: 3±16. # Munksgaard 2000.

Recent studies have identi®ed various herpesviruses in human periodontal

disease. Epstein±Barr virus type 1 (EBV-1) infects periodontal B-lymphocytes
and human cytomegalovirus (HCMV) infects periodontal monocytes/
macrophages and T-lymphocytes. EBV-1, HCMV and other herpesviruses are
present more frequently in periodontitis lesions and acute necrotizing ulcerative
gingivitis-lesions than in gingivitis or periodontally healthy sites. Reactivation of
HCMV in periodontitis lesions tends to be associated with progressing
periodontal disease. Herpesvirus-associated periodontitis lesions harbor
elevated levels of periodontopathic bacteria, including Actinobacillus
actinomycetemcomitans, Porphyromonas gingivalis, Bacteriodes forsythus,
Prevotella intermedia, Prevotella nigrescens and Treponema denticola. It may be
that active periodontal herpesvirus infection impairs periodontal defenses,
thereby permitting subgingival overgrowth of periodontopathic bacteria.
Alteration between latent and active herpesvirus infection in the periodontium
might lead to transient local immunosuppression and explain in part the episodic Jùrgen Slots, University of Southern California,
progressive nature of human periodontitis. Tissue tropism of herpesvirus School of Dentistry, MC-0641, Los Angeles, CA
infections might help explain the localized pattern of tissue destruction in 90089±0641, USA
periodontitis. Absence of herpesvirus infection or viral reactivation might Key words: herpesvirus; human
explain why some individuals carry periodontopathic bacteria while still cytomegalovirus; Epstein±Barr virus; herpes
maintaining periodontal health. Further studies are warranted to delineate simplex virus; polymerase chain reaction;
whether the proposed herpesvirus-periodontopathic bacteria model might periodontal disease
account for some of the pathogenic features of human periodontal disease. Accepted for publication June 28, 1999

Most human viruses known to cause oral diseases
are DNA viruses that are contracted in childhood
or early adulthood through contact with blood,
saliva or genital secretions (1). Herpesviruses seem
to be the most important DNA viruses in oral
pathology. The hallmark of herpesvirus infections
is immune impairment. Active herpesvirus infec-
tions may have particularly severe consequences
in HIV-infected and other immunocompromised
individuals.
Eight herpesvirus species have been identi®ed
(Table 1). Oral disease has been attributed to
herpes simplex virus (HSV) type 1 (2, 3), HSV type
2 (3, 4), varicella-zoster virus (VZV) (5, 6),
Epstein±Barr virus (EBV) (3, 7), human cyto-
megalovirus (HCMV) (2, 8, 9) and human herpes
virus 8 (HHV-8) (10). Active herpesvirus infection
in the oral cavity often involves ulceration of
gingiva (3, 7, 11). Recent studies have implicated
EBV-1 and HCMV in the pathogenesis of human
periodontal disease (12, 13). The present review
describes the association between herpesviruses
and periodontal disease and discusses possible
mechanisms by which herpesviruses might con-
tribute to periodontal disease.
General description of herpesviruses
Herpetoviridae
The Herpetoviridae family contains only the genus
Herpesvirus. Herpesviruses share at least four
characteristics: 1) the typical particle morphology
consists of an icosahedral capsid assembly of 162
capsomers enclosed in a viral envelope; 2) the
genome comprises a single double-stranded DNA
molecule ranging in size from 120 to 250 kbp; 3)
4 Contreras & Slots

Table 1. The human herpesviruses

Herpes Genome size Guaninez

Human herpesviruses Abbreviation group Most commonly associated illness kbp cytosine
Herpes simplex virus type 1 HSV-1 a Cold sores 152 68.3
Herpes simplex virus type 2 HSV-2 a Genital lesions 155 70.4
Varicella-zoster virus VZV a Chicken pox/shingles 125 46
Epstein±Barr virus EBV c Glandular fever (Burkitt's lymphoma, 172 60
nasopharyngeal carcinoma)
Cytomegalovirus HCMV b Congentital abnormalities w229 57
Human herpesvirus 6 HHV-6 b Infant rash exanthem subitum 159 42
Human herpesvirus 7 HHV-7 b Febrile illnesses 145 45
Kaposi's sarcoma herpesvirus KSHV, HHV-8 c Kaposi's sarcoma 160±170

viral infection exhibits tendency to tissue tropism;
i.e. highly selective in regard to the surfaces or
organs that they infect or invade; and 4) the viral
productive phase is followed by a latent phase in
host cells which ensures survival of the viral
genome throughout the lifetime of the infected
individual. Occasionally, latent herpesviruses can
undergo reactivation and re-enter the productive
phase (1, 14, 15).
Table 1 lists the 8 known human herpesvirus
species and the a, b or c subgroups (1, 16). Table 1
also describes common illnesses associated with
herpesviruses. The alpha group (subfamily Alpha-
herpesvirinae) includes HSV-1, HSV-2 and VZV.
The beta group (subfamily Betaherpesvirinae)
includes HCMV, human herpesvirus 6 (HHV-6)
and human herpesvirus 7 (HHV-7). The gamma
group (subfamily Gammaherpesvirinae) includes
EBV and HHV-8 or Kaposi's sarcoma herpesvirus.
In latency, HSV-1, HSV-2 and VZV reside in
sensory nerve ganglia and monocytes (1, 15, 17),
EBV in B-lymphocytes and salivary gland tissue
(18±21), HCMV in monocytes, macrophages,
lymphocytes and salivary gland tissue (15, 22±29),
HHV-6 in lymphocytes and ductal epithelium of
salivary gland tissue (30±32), HHV-7 in lympho-
cytes and salivary gland tissue (33, 34) and HHV-8
in lymphocytes and macrophages (35, 36).
Activation of latent herpesvirus infections can
cause symptomatic or asymptomatic recurrent
infection (3, 11, 15, 37). Physical trauma, stress,
immunosuppression, immune dysfunction and
radiotherapy may trigger viral reactivation (2, 22,
38).
Structure and organization of herpesvirus genome
Extensive DNA sequence information exists for
human herpesviruses, including complete genomic
sequence of seven herpesviruses. Human herpes-
viruses share homologous genes and blocks of
conserved genes. It has been suggested that
conserved genes grouped in blocks, the so-called
herpesvirus core, de®ne the herpesviruses as a virus
family (39). Several genes in the conserved core
regions encode proteins characteristic of herpes-
viruses. In general, herpesvirus species of the same
subfamily share the greatest number and exhibit
the closest alignment of homologous genes. Seven
blocks of genes that are conserved among all
herpesvirus subfamilies are located in the center of
most human herpesvirus genomes. Interestingly,
although latency is a biological characteristic of
herpesviruses, the few known latency genes and
transcripts are not located in the conserved core
region and are not conserved among the herpes-
virus subfamilies.
Herpesvirus species differ greatly in genomic
size, sequence arrangement and base composition.
Human herpesvirus genome sizes range from
125 kbp for varicella-zoster virus (40) to 230 kpb
for cytomegalovirus (39). The genomic size of
individual isolates of the same species can vary as
much as 10 kpb, dependent on the number of
terminal or internal repeat sequences. Presence of
terminal and internal sequence repetitions gives
rise to multiple genomic isomers.
The nucleotide composition varies considerably
among human herpesviruses. For example,
guanine-cytosine content in the Alphaherpes-
viruses HSV and VZV is 68% and 46%, respec-
tively (40, 41). Presumably, DNA base composition
of herpesviruses depends upon ability of individual
viruses to modulate the available nucleotide pool
in the cell and upon tissue speci®c effects on virus
DNA replication (42).
Herpesvirus proteins
Herpesviruses encode many of the proteins neces-
sary for viral DNA replication. Herpesvirus genes
essential for viral origin-dependent DNA replica-
tion have been identi®ed, including genes for DNA
polymerase, genes for an origin-binding protein
and genes for a helicase/primase complex (43, 44).
Herpesviruses also encode proteins involved in

nucleotide metabolism and DNA repair. One
example is thymidine kinase encoded by HSV,
VZV and EBV (41). HCMV or HHV-6/-7 do not
possess thymidine kinase gene or homolog genes
(39, 45). However, HCMV encodes another type of
protein kinase (UL97), which is conserved among
all the herpesviruses, including viruses possessing a
thymidine kinase gene. In HSV, the thymidine
kinase is responsible for ganciclovir phosphoryla-
tion (1). In HCMV, UL97 protein kinase phos-
phorylates ganciclovir (46).
Herpesviruses express several genes in the mode
of a cascade that, for convenience, can be divided
into immediate±early, early and late phases.
Immediate±early transcripts are mainly regulatory
proteins, whose function is to transactivate later
stages.
Herpesvirus genes encode numerous glyco-
proteins expressed on the surface of the infected
cell and the viral envelope, some of which are
conserved among all human herpesviruses (1, 47).
Structural glycoproteins mediate entry into suscep-
tible cells, cell-to-cell viral spread and serve as
major determinants of tissue tropism and host
range. Glycoprotein B facilitates viral entry into
cells and glycoproteins gH and gL viral cell-to-cell
spread (1, 48). Herpesviruses also encode the entire
set of proteins necessary for assembly of the
icosahedral capsid.
In summary, comparison of herpesvirus genes
has provided insights into the function of encoded
proteins and the evolutionary relatedness of the
various herpesvirus species. It seems clear that
genes conserved among the species encode several
basic biological characteristics of Herpesviridae.
What is not clear is the identity and function of
genes that are not conserved among the 3
herpesvirus subfamilies and which are likely to
be responsible for the biological diversity of
herpesviruses.
Herpesvirus species
Herpes simplex virus type 1 and 2
HSV-1 causes mainly oral infections and HSV-2
ano-genital infections. Although HSV-1 is respon-
sible for most cases of herpetic gingivostomatitis,
HSV-2 may occasionally be involved (3, 4, 49).
HSV-1 and HSV-2 are also implicated in recurrent
erythema multiforme, Behcet's syndrome, some
oral ulcers and oral squamous carcinoma (11, 50).
Viral shedding is most common in immunocom-
promised people. However, 5±8% of children and
2±10% of adults periodically shed infectious HSV
in saliva even in the absence of clinical disease (51).
HSV can be transmitted through direct contact
Herpesviruses in periodontitis 5
with HSV lesions or via infected saliva or other
secretions (52).
HSV is recovered from persistent oral ulcers in
more than 30% of HIV-positive patients (53).
Flaitz et al. (2) detected HSV in 19%, HCMV in
53% and co-infection of HSV and HCMV in 28%
of HIV-positive patients with persistent ulcers.
Treatment with systemic acyclovir and ganciclovir
resulted in lesion resolution in all but 1 case.
Acyclovir has been recommended in the treat-
ment of various forms of recurrent HSV-1 and
HSV-2 infections but the drug appears more
effective in the management of genital herpes
than of oral herpes lesions. However, in immuno-
compromised individuals oral HSV lesions are
quite responsive to acyclovir in the presence of
acyclovir-susceptible viral strains (53).
Varicella-zoster virus (VZV)
VZV causes varicella (chickenpox) as primary
infection, affecting mainly children, whereas
VZV reactivation in adults causes herpes zoster
(shingles). Varicella is a highly infectious disease
transmitted by inhalation of infective droplets or
by direct contact with lesions. VZV-associated
disease is generally benign in children and tends to
be more severe in adults. Oral lesions include
vesicles on the lips, and hard and soft palate (17,
54). Both primary and secondary VZV infection
can produce gingival lesions (3, 6). Following
primary infection, VZV remains latent in the
dorsal root ganglion cells for possibly later
reactivation.
Herpes zoster results from reactivation of latent
VZV. Vesicles quickly break to form ulcerated
lesions with prominent red borders, resembling
aphthous ulcers. Lesions are unilaterally distrib-
uted along the infected nerve (17, 54). Herpes
zoster occurs more frequently in elderly individuals
and may signal the presence of systemic disease.
There is a preference for the maxillary or
mandibular branches of the nerve when reactiva-
tion occurs from the trigeminal ganglion, and oral
and gingival ulcerations are usually present (17).
Herpes zoster may also give rise to necrosis of the
periodontium and mandibular bone, dental hypo-
plasia and retarded tooth eruption (5, 55). A major
effect of VZV activation is altered cell-mediated
immunity (56, 57).
Immunocompromised individuals, including
HIV-infected individuals, experience an increased
incidence and recurrence of herpes zoster infection
(2, 58). Varicella may appear in HIV-positive
patients as an atypical, persistent form of the
disease. Clinical presentation and occurrence of
6 Contreras & Slots
complications from VZV reactivation are related
to severity of immunode®ciency (55).
Antiviral drugs [acyclovir, valacyclovir and
famciclovir (51, 59)] are effective in reducing the
duration of VZV disease and adverse events from
secondary infections. Antiviral drugs are indicated
in the early disease stages. Treatment with
intravenous acyclovir and foscarnet has been
effective in controlling HIV-associated herpes
zoster (17, 54).
Epstein±Barr virus
EBV infects and replicates in oral and orophar-
yngeal epithelium and in B-lymphocytes (11, 19, 20,
29, 60). Blood or saliva transmits EBV. In
developing countries EBV infects most children,
usually asymptomatically, before the age of 2 yr. In
developed countries primary EBV infection occurs
mainly in adolescents, and often in the form of
infectious mononucleosis (61).
Symptoms of infectious mononucleosis include
fever, lymphadenopathy, malaise and sore throat
(pharyngitis). Oral ulcers, multiple palatal petechia
and, infrequently, pericoronitis, acute ulcerative
gingivitis or gingival ulcerations have been
reported (3, 7, 11). Acyclovir is not effective in
treating mononucleosis.
At least 2 EBV types exist: EBV type 1 and type
2. EBV-1 predominates in the western hemisphere
and EBV-2 in Africa (3, 21). HIV-infected
individuals experience frequent EBV-2 infection
or dual EBV-1 and EBV-2 infections (62, 63).
Latent EBV infection can be reactivated, leading
to viral shedding into oral mucosa. EBV-infected
epithelial cells may cause oral hairy leukoplakia in
HIV-positive patients (62, 64). There is evidence of
EBV replicating within epithelial cells of oral hairy
leukoplakia lesions (62). The appearance of oral
hairy leukoplakia in HIV-positive patients may be
suggestive of development of AIDS (64, 65).
However, oral hairy leukoplakia can appear in
the absence of HIV infection and can be found in
patients who are immunosuppressed for reasons
other than HIV (66, 67). Additionally, oral lesions
similar to oral hairy leukoplakia can occur in
patients who show no evidence of EBV infection
(68).
EBV may cause malignancy, including naso-
pharyngeal carcinoma (21, 69), Burkitt's lym-
phoma (21), B-cell lymphoma (70) and oral
carcinomas (71). Oral non-Hodgkin's lymphoma
may involve gingiva (72, 73), causing tooth mobility
and tooth exfoliation (74, 75). Midline granuloma
is an EBV-associated lymphoma (76, 77) that can
cause severe gingival and periodontal destruction.
Human cytomegalovirus
HCMV is detected in blood and in many body
secretions including semen, maternal milk and
saliva. HCMV is a ubiquitous herpesvirus, usually
acquired in early childhood. Most primary infec-
tions are asymptomatic and the site of HCMV
latency is not known, although the virus is often
recovered from salivary glands (24). HCMV may
target endothelial and ductal epithelial cells (22,
25±28, 78) and can also infect gingival monocytes/
macrophages and T-lymphocytes (29). HCMV is
emerging as an important opportunistic pathogen
in immunocompromised individuals, especially
those with AIDS and transplant patients (38, 79).
AIDS patients may be infected with multiple
HCMV strains (80) and are at risk of disseminated
HCMV infection.
HCMV infection produces 3 recognizable clin-
ical syndromes: perinatal disease and HCMV
inclusion disease (26, 81), acute acquired HCMV
infection (26) and disease in the immunocompro-
mised host (81). Perinatal HCMV disease of infants
whose mothers had a primary infection during
pregnancy present microcephalia associated with
mental retardation and hearing impairment.
HCMV infection acquired neonatally resembles
infectious mononucleosis or may progress asymp-
tomatically. The second HCMV-related syndrome
is similar to infectious mononucleosis except for
absence of pharyngitis and heterophilic antibodies.
The third syndrome is observed in immuno-
compromised individuals, including HIV-infected
individuals and tissue and bone marrow trans-
plant patients. HCMV infection can enhance the
immunosuppressiveness of HIV and aggravate
opportunistic infections (9, 26, 38, 54).
Oral ulcerations in immunosuppressed patients
are often related to HCMV (2, 53, 75, 82, 83). In
HIV-positive patients, 53% of persistent ulcers
showed HCMV and another 28% HCMV and
HSV co-infection (2). HCMV-related oral ulcers
can occasionally involve gingiva and periodontium
with underlying bone destruction or osteomyelitis
(8, 82, 84, 85). HCMV-infection may also give rise
to gingival hyperplasia (86).
Human herpesvirus 6
HHV-6 was originally named human B-lympho-
tropic virus (30, 87) but was recently reclassi®ed
as herpesvirus (88). The 2 variants (A and B)
identi®ed (89) have af®nity for CD4zlymphocytes
(90). HHV-6 infects ductal epithelium of salivary
glands and is isolated from saliva of most
individuals (90). It can also occur in gingiva of
periodontitis lesions (91). In infants, HHV-6 may

cause roseola (exanthema subitum or sixth disease)
which is a self-limiting condition, showing mild skin
exanthema and fever (90). HHV-6 is also suspected
of causing mononucleosis, pneumonia, meningitis,
encephalitis and being a co-factor of accelerated
immunosuppression in HIV-infected individuals.
HHV-6 infection can induce proliferation of CD4z
and CD8z lymphocytes and natural killer cells,
thereby increasing the severity of HIV infection
(92). HHV-6 may cause short-lived febrile illnesses
and hepatitis in previously healthy individuals,
as well as prolonged febrile illness in immuno-
suppressed patients (88).
HHV-6 may be responsible for some cases of
mononucleosis not associated with EBV or
HCMV, although it is not clear if the active
HHV-6 infection observed is the cause or the result
of the disease (90). Co-infection of HHV-6 and
EBV has been related to acute infectious mono-
nucleosis (93).
HHV-6 may be involved in oral squamous
carcinoma (90). In a study of 51 squamous cell
carcinomas, 18 non-malignant lesions and 7 normal
mucosa samples, HHV-6 was detected in 79% of
malignancies, in 67% of lichen planus lesions and
leukoplakia, but was absent in normal mucosa (90).
HHV-6 variant B was detected in 60% of the
squamous carcinoma lesions (90).
HHV-6 was implicated recently in the pathogen-
esis of multiple sclerosis (94). Multiple sclerosis
patients present elevated levels of serum anti-
HHV-6 antibodies compared to controls (95).
Although HHV-6 is present in brains of virtually
all adults (96), particularly in neurons and glial cells
(97), it is also found in the nuclei of brain
oligodendrocytes associated with multiple sclerosis
plaques (97).
Human herpesvirus 7
HHV-7 is a ubiquitous herpesvirus. It is closely
related to HHV-6 and the two Betaherpesviruses
exhibit serological cross-reactivity with each other
(32). HHV-7 infection is usually acquired in
childhood and most adults are HHV-7 seropositive.
HHV-7 is found in saliva, which presents the major
mode of transmission, and is secreted for many
years following initial infection (98). Transmission
has been detected from a grandparent to a parent
to a child (98). Minor labial salivary glands often
harbor HHV-7 and may sometimes be the site of
viral replication (89). In a study of more than 100
specimens from major salivary glands, HHV-7 was
detected in 100% of submandibular, in 85% of
parotid and in 59% of minor lip salivary gland
samples (99). HHV-7 has also been detected in
in¯amed gingiva (91).
Herpesviruses in periodontitis 7
HHV-7 appears to be associated with at least 2
pathological conditions: roseola and pityriasis
rosea. Patients recovering from roseola exhibit
seropositivity to both HHV-6 and HHV-7 (100).
Plasma of patients with pityriasis rosea may show
HHV-7 DNA (101). Pityriasis rosea is a self-
limiting exanthema that is characterized by crops
of masculopapular pale-red oval cutaneous lesions
which may last for up to 2 wk. Lesions of the
tongue and cheek have been reported in pityriasis
rosea (102). There is evidence that infections
misdiagnosed as measles and rubella might, in
reality, have been primary infections of HHV-6 or
HHV-7 (102).
Human herpesvirus 8
Newly discovered, HHV-8 is believed to be the
key agent of Kaposi's sarcoma. HHV-8 DNA
sequences were identi®ed in 53 of 54 AIDS-related
oral Kaposi's sarcoma lesions (10). HHV-8 DNA
has also been identi®ed in body-cavity-based non-
Hodgkin's lymphomas, in Castleman's disease and
in anti-immunoblastic lymphadenopathy (35, 96,
103). HHV-8 has been identi®ed in periodontitis
lesions of HIV-positive patients (91). Serological
studies indicate the presence of HHV-8 in 25% of
the adult US population and in about 8% of
children (104).
Kaposi's sarcoma was originally described as a
rare vascular malignant tumor occurring in elderly
men of mainly Mediterranean, Eastern European
or Middle Eastern descent. With the advent of the
AIDS epidemic, Kaposi's sarcoma has become
relatively prevalent, although the disease can also
occur with dermal bullous pemphigoid in HIV-
negative immunosuppressed patients (105). Appar-
ently, immunosuppression serves to activate a
latent HHV-8 infection with subsequent develop-
ment of Kaposi's sarcoma, which is the most
common neoplastic disease in AIDS patients.
Kaposi's sarcoma debuts in the oral cavity in
60% of patients and may later progress to extraoral
sites (10). Oral Kaposi's sarcoma frequently
involves oral keratinized mucosa. The most
common oral site is the palate, followed by
attached gingiva. Also, Kaposi's sarcoma may
progress from gingiva to the underlying alveolar
bone. Oral Kaposi's sarcoma lesions become
symptomatic in 25% of patients (106).
Association between herpesviruses and perio-
dontal disease
The literature presents only few data on herpes-
viruses in periodontal disease. Sabiston (107)
suggested an association between HCMV and
8 Contreras & Slots
acute necrotizing ulcerative gingivitis (ANUG);
however, he did not present experimental evidence
to support his hypothesis. Other authors presented
case-reports that also proposed a relationship
between herpesviral infection and ANUG (108,
109). In in¯ammatory cells of juvenile periodontitis
gingival biopsy specimens, Burghelea & Serb (110,
111) described the presence of nuclear body-type
structures and virus-like inclusions which, consi-
dering recent ®ndings by Ting et al. (112), might
have been herpesviruses. In 1994, Contreras (113)
assessed the presence of cultivable HSV in monthly
salivary samples from 9 patients with advanced, 10
patients with moderate and 11 patients with slight
periodontitis. Salivary HSV was demonstrated in 4
(44%) advanced periodontitis patients, in 2 (20%)
moderate periodontitis patients and in none of the
slight periodontitis patients.
Recently, Contreras and coworkers employed a
sensitive and speci®c nested polymerase chain
reaction (PCR) detection method to study herpes-
viruses in periodontal sites (13). The PCR proce-
dures used are outlined elsewhere (12, 13, 114, 115,
116).
Table 2 describes the distribution of herpesviruses
in gingival biopsy specimens from 25 adult study
subjects. EBV-1 was only detected in 3 and HCMV
in 2 specimens from healthy gingiva. In contrast, 2±6
herpesviruses were demonstrated in the 14 gingival
biopsy samples from adult periodontitis lesions.
HSV, EBV-1, EBV-2, HCMV and HHV-7 showed
signi®cant associations with periodontitis. HHV-6
and HHV-8 occurred only in gingival biopsy samples
of periodontitis lesions. Three of 4 gingival biopsy
samples yielding HHV-8 originated from patients
with con®rmed HIV infection.
Other studies from our laboratory have also
related EBV-1 and HCMV to adult periodontitis
(12, 13). Contreras & Slots (117) even showed that
periodontitis lesions might be associated with
active HCMV infection, as determined by means
of cDNA analysis for major capsid protein
transcripts.
Table 2. Herpesviruses in gingival biopsies from periodontal
health and periodontitis (91)
Periodontal health Periodontitis p-values
Viruses (11 subjects) (14 subjects) (chi-square test)
HSV 1 (9)a 8 (57) 0.04
EBV-1 3 (27) 11 (79) 0.03
EBV-2 0 (0) 7 (50) 0.02
HCMV 2 (18) 12 (86) 0.003
HHV-6 0 (0) 3 (21) 0.31
HHV-7 0 (0) 6 (43) 0.04
HHV-8 0 (0) 4 (29)b 0.17
a
No. (%) virally positive samples. b3 patients were con®rmed
HIV-positive.
In adult periodontitis lesions, HSV infects
T-lymphocytes and monocytes/macrophages,
EBV-1 infects B-lymphocytes and HCMV infects
monocytes/macrophages and T-lymphocytes (29).
Herpesvirus-infected in¯ammatory cells may exert
diminished ability to defend against bacterial
challenge.
Table 3 shows the occurrence of periodontal
EBV and HCMV in 11 localized juvenile perio-
dontitis (LJP) patients, aged 10±23 years. Each
patient contributed a pooled subgingival sample
from 3 gingivitis/healthy sites around canines (2±
3 mm periodontal pocket depth) and a pooled
subgingival sample from 3 LJP lesions around ®rst
molar and incisor teeth (5±11 mm periodontal
pocket depth). Of the 11 samples from normal
periodontal sites, HCMV was detected in 2, EBV-1
in 2, HSV in 1 and viral co-infection in 2. Of the 14
LJP samples, HCMV was detected in 8, EBV-1 in
7, EBV-2 in 1, HSV in 6 and viral co-infection in 8.
The difference in occurrence of HCMV and viral
co-infection between normal and diseased perio-
dontal sites was statistically signi®cant (p~0.031).
Ronderos et al. (118) recently con®rmed the strong
association between HCMV and juvenile perio-
dontitis in a study of adolescents from Jamaica.
HCMV activation was detected in LJP lesions of
all 5 HCMV-positive patients aged 10±14 years
(early LJP), compared to only in 1 of 3 patients
older than 14 years (Table 3). All LJP samples that
reveal HCMV activation originated from sites
showing absence of radiographic crestal alveolar
lamina dura, a feature associated with progressing
periodontal disease (119). Samples from shallow/
non-progressing periodontal sites showed no evi-
dence of HCMV activation. Also, 2 older LJP
patients who revealed latent HCMV infection
exhibited radiographic evidence of non-progres-
sing disease. These data link active periodontal
HCMV infection to disease-active LJP. Microbio-
logically, LJP lesions showing HCMV activation
harbored relatively high levels of the periodontal
pathogen Actinobacillus actinomycetemcomitans.
Preus et al. (120) related rapidly progressing LJP to
the subgingival presence of 2 types of virions,
suggestive of active viral infection, but assumed the
viruses to be A. actinomycetemcomitans-associated
bacteriophages. We hypothesize that active perio-
dontal HCMV infection initiates overgrowth of
subgingival A. actinomycetemcomitans, resulting in
periodontal breakdown.
Velazco et al. (121) studied an 11-year-old girl
exhibiting Papillon±LefeÁvre syndrome, including
hyperkeratosis palmo-plantaris and severe perio-
dontitis resembling LJP. Periodontitis lesions in
the Papillon±LefeÁvre syndrome patient revealed
subgingival EBV-1 and HCMV as well as
 Herpesviruses in periodontitis 9

Table 3. Human cytomegalovirus (HCMV), Epstein±Barr type 1 virus (EBV-1) and A. actinomycetemcomitans in localized juvenile
periodontitis (LJP) (112)

HCMV mRNA
major capsid A. actinomycetemcomitans
HCMV DNA protein EBV-1 in LJP sites
Radiographic crestal
Patient no. % of total PCR alveolar lamina dura
(age in years) LJP Control LJP Control LJP Control viable counts detection in LJP sites
1 (10) z z z Ð z z 0.6 z Not readable
2 (12) z Ð z Ð Ð Ð 2.6 z Ð
3 (12) z Ð z Ð z Ð Not done z Ð
4 (14) z z z Ð z z 4.2 z Ð
5 (14) z Ð z Ð z Ð Not done z Ð
6 (14) Ð Ð Not done Not done z Ð 0 Ð z
7 (15) z Ð Ð Ð z Ð Not done Ð z
8 (16) z Ð z Ð Ð Ð 0.3 z Ð
9 (19) Ð Ð Not done Not done Ð Ð 0 Ð z
10 (20) z Ð Ð Ð Ð Ð 0 Ð Not readable
11 (23) Ð Ð Not done Not done z Ð 0 Ð z
p-value 0.031 0.031 0.063 Ð 0.036a 0.17b
a
Presence of A. actinomycetemcomitans in HCMV active vs. non-active sites (Fisher exact test). bAbsence of crestal alveolar lamina
dura in HCMV active vs. non-active sites (Fisher exact test).

A. actinomycetemcomitans. In Papillon±LefeÁvre HSV and 1 (5%) HHV-6. 8 (36%) ANUG children

syndrome-periodontitis, Preus et al. (122) identi®ed
4 morphologically distinct viruses in actively
progressing lesions but, interestingly, detected no
viruses in arrested periodontitis lesions or in
healthy periodontal sites. As with LJP, Preus
et al. considered the observed viruses to be
A. actinomycetemcomitans bacteriophages. How-
ever, some of the subgingival viruses observed by
Preus et al. (120) resembled morphologically
herpesviruses.
Contreras et al. (123) studied the relationship
between subgingival herpesviruses and acute
necrotizing ulcerative (ANUG) in malnourished
and well-nourished Nigerian children, aged 3±14
years (Table 4). Only 2 of 20 (10%) children in the
normal oral health/malnourished subject group and
2 of 20 (10%) children in the normal oral health/
non-malnourished subject group revealed subgin-
gival herpesviruses. No ANUG-free children
showed herpesviral co-infection. In contrast, of
22 malnourished ANUG patients, 13 (59%)
demonstrated HCMV, 6 (27%) EBV-1, 5 (23%)
revealed viral coinfection, including 5 children with
HCMVzEBV-1, 1 child with HCMVzEBV-
1zHSV, 1 child with HCMVzHHV-6zHSV
and 1 child with HCMVzHSV. No child revealed
HIV-1 or EBV-2. Contreras et al. (123) proposed
that herpesviruses together with malnutrition and
pathogenic periodontal bacteria be important
determinants in the development of ANUG in
Nigerian children.
Similarly to medical infections, in which herpes-
virus can reduce the host defense and give rise to
overgrowth of pathogenic microorganisms (124,
125, 126), herpesvirus-infected periodontal sites
seem to be associated with increased levels of
periodontal pathogens. As described above, LJP
lesions experiencing active HCMV infection har-
bored relatively high A. actinomycetemcomitans
counts (112). In adult periodontitis, Contreras et al.
(127) showed an association between subgingival
EBV-1 and HCMV, and elevated levels of the
periodontal pathogen Porphyromonas gingivalis
and other putative pathogens, including Bacter-

Table 4. Detection of herpesviruses in ANUG lesions and normal periodontal sites of Nigerian children with and without
malnutrition (123)a

Normal oral health Normal oral health p-values for ANUG

z no malnutrition ANUGzmalnutrition z malnutrition vs. ANUG-free
Viruses (n~20 subjects) (n~22 subjects) (n~20 subjects) controlsb
Any test virus 2 (10%) 15 (68%)c 2 (10%) v0.001
HCMV 1 (5%) 13 (59%) 0 0.001
EBV-1 1 (5%) 6 (27%) 1 (5%) 0.035
HSV 0 5 (23%) 0 0.028
Viral co-infection 0 8 (36%) 0 v0.001
a
No samples yielded EBV-2, HPV, or HIV-1. bChi-square test. cNo. of positive subjects (% positive subjects in the group).
10 Contreras & Slots
iodes forsythus, Prevotella intermedia, Prevotella
nigrescens and Treponema denticola (Table 5).
Herpesviruses may also interfere with perio-
dontal healing. In guided tissue regeneration,
Smith MacDonald et al. (128) found that 4
periodontal sites showing either EBV-1 or
HCMV had an average gain in clinical attachment
of 2.3 mm compared with 16 virally negative sites
that showed a mean clinical attachment gain of
5.0 mm (p~0.004). By infecting and altering
functions of ®broblasts (13, 128), herpesviruses
may reduce the regenerating potential of the
periodontal ligament.
Pathogenesis of herpesvirus-associated perio-
dontal disease
Available data are consistent with herpesviruses
participating in the etiology and pathogenesis of
some aggressive types of human periodontal
disease. Herpesviruses may cause periodontal
pathology as a direct result of virus infection and
replication, or as a result of virally mediated
damage to the host defense. Herpesviruses may
exert periodontopathic potential through at least 5
mechanisms, operating alone or in combination.
First, herpesviruses may cause direct cytopathic
effects on ®broblasts, keratinocytes, endothelial
cells (21, 26, 37), on in¯ammatory cells such as
polymorphonuclear leukocytes (124, 126, 129, 130),
lymphocytes (14, 130), macrophages (14, 37), and
possibly on bone cells (131). Since the above cells
are key constituents of in¯amed periodontal tissue,
herpesvirus-induced cytopathic effects may
hamper tissue turnover and repair.
Secondly, herpesviral periodontal infections may
impair cells involved in host defense, thereby
predisposing to microbial superinfection. HCMV
and EBV-1 can infect and/or alter functions of
Table 5. Relationship between periodontal Epstein±Barr
virus type 1 (EBV-1) and cytomegalovirus (HCMV) and
occurrence of subgingival pathogenic bacteria (127)
Explanatory variables Odds ratios p-values
EBV-1
P. gingivalis 3.37 0.010
P. gingivaliszB. forsythus 3.84 0.006
P. gingivaliszP. intermedia 4.03 0.005
P. gingivaliszT. denticola 4.17 0.004
P. gingivaliszB. forsythusz 4.06 0.005
T. denticola
HCMV
P. gingivaliszP. nigrescens 3.23 0.01
P. gingivaliszP. nigrescensz 2.59 0.05
T. denticola
P. gingivaliszB. forsythusz 3.23 0.01
P. nigrescens
monocytes, macrophages (14, 18, 27, 124, 132) and
lymphocytes (24, 26, 61, 133±135). As described
above, herpesvirus genomes are present in in¯am-
matory cells of adult periodontitis lesions (29).
Thirdly, gingival herpesvirus infection may
promote subgingival attachment and colonization
of periodontopathic bacteria, similar to the
enhanced bacterial adherence to virus-infected
cells observed in medical infections (19, 125, 136±
138). Viral proteins expressed on eukaryotic cell
membranes can act as bacterial receptors and
generate new bacterial binding sites (139, 140).
Also, loss of virus-damaged epithelial cells can
expose the basement membrane and the surface of
regenerating cells, providing new sites for bacterial
binding (141±144).
Fourthly, herpesviral infections can give rise to
altered in¯ammatory mediator and cytokine
responses (18, 61, 131, 145±152). In periodontitis,
HCMV-induced expression of cytokines is parti-
cularly intriguing (153,154). HCMV infection can
upregulate interleukin 1-beta (IL-1b) and tumor
necrosis factor-alpha (TNF-a) gene expression of
monocytes and macrophages (135, 147±149).
Increased production of the proin¯ammatory
cytokines IL-1b and TNF-a by macrophages and
monocytes has been associated with enhanced
susceptibility to destructive periodontal disease
(153±155). In turn, IL-1b and TNF-a may up-
regulate matrix metalloproteinase (156±164),
downregulate tissue inhibitors of metalloprotei-
nase (155, 163±165) and mediate periodontal bone
destruction (162±164, 166).
EBV and other members of the Herpesviridae
family elaborate compounds that may exert impor-
tant regulatory effects on host cell cytokine synth-
esis. EBV-encoded protein BCRF1 possesses a
striking structural and functional similarity with
IL-10 (151), which can suppress TH1 cell-mediated
IL-2, interferon-c and lymphotoxin production and
polarize the immune system toward a TH2-type
response (18, 61, 153). TH1-type response has been
associated with protection against periodontitis
(156, 161, 165, 166) whereas TH2-type seems to be
related to progressive periodontal disease (167±
170). In addition, EBV infection of B-lymphocytes
can induce a shift in lymphocyte subpopulations
toward predominance of B-lymphocytes/plasma
cells (168). EBV-mediated transformation of B-
lymphocytes to plasma cells may occur in perio-
dontal disease as evidenced by a B-lymphocyte
dominance and polyclonal B-lymphocyte activation
in periodontitis lesions (160, 166, 169). B-lympho-
cytes/plasma cells are particularly prominent in
progressive periodontitis lesions (170, 171).
Contreras et al. (29) detected HSV in T-
lymphocyte and in monocyte/macrophage fractions

from adult periodontitis tissue specimens. HSV
infection of these cells may constitute an important
immune evasive mechanism (37, 151). By infecting
T-lymphocytes, HSV may downregulate important
T-lymphocyte functions (172, 173). The rapid
periodontal breakdown seen in some HIV patients
with decreased T-helper cell response may suggest
a protective function of T-lymphocytes in perio-
dontal disease (75, 130, 174, 175). Conceivably,
local disruption of periodontal T-lymphocyte
functions by HSV may increase the risk for
destructive periodontal infections.
Fifthly, herpesviruses can produce tissue injury
as result of immunopathological responses to
virally infected cells (18, 25, 37, 61). HCMV and
HSV can induce cell-mediated immunosuppression
by reducing the cell surface expression of MHC
(major histocompatibility complex) class I mole-
cules, thereby interfering with T-lymphocyte
recognition (14, 26, 176±178). HCMV can cause
metabolic abnormalities in lymphocytes and mono-
cytes (25, 26, 172, 176). In addition, HCMV can
suppress antigen-speci®c cytotoxic T-lymphocyte
functions, resulting in decreases in circulating
CD4z cells and increases in CD8z suppressor
cells, which in turn may lead to global impairment
of cell-mediated immunity (133, 176, 177). EBV
may trigger a proliferation of cytotoxic T-lympho-
cytes capable of recognizing and destroying virally
infected cells (18, 21, 153, 179). Moreover, acute
EBV infection and infectious mononucleosis can
induce polyclonal B-lymphocyte activation with
generation of anti-neutrophil antibodies and neu-
tropenia (179). EBV-infected B-lymphocytes may
shed viral structural antigens that result in produc-
tion of blocking antibodies, immune complex
formation and T-suppressor cell activation (61,
151, 146, 147). EBV can also suppress T-lympho-
cyte functions (146). Immunopathological reac-
tions similar to those associated with herpesvirus
infections have been implicated in the pathogenesis
of human periodontal disease (180, 181).
Conclusions and perspectives
This paper presents a novel concept of the
pathogenesis of human periodontal disease. Our
data implicate certain herpesviruses in the etiology
and/or pathogenesis of human periodontal disease
based on: 1) the presence of nucleic acid sequences
of EBV-1 and HCMV and other herpesviruses in
juvenile and adult periodontitis lesions; 2) the
association between herpesviruses and acute
necrotizing gingivitis in malnourished Nigerian
children; 3) the demonstration of mRNA late
gene HCMV expression in adult and localized
Herpesviruses in periodontitis 11
juvenile periodontitis lesions and the apparent
association with progressive disease; 4) the
demonstration of increased frequency of perio-
dontopathic bacteria in herpesvirally positive
periodontitis lesions; 5) the detection of nucleic
acid sequences of herpesviruses in in¯ammatory
periodontal cells; 6) the probable profound effect
of herpesvirus infection on periodontal defense
cells; and 7) the ability of herpesviruses to augment
the expression of tissue-damaging cytokines in
periodontal in¯ammatory cells.
We suggest that gingival infection with certain
herpesviruses decrease the resistance of the
periodontal tissue, thereby permitting subgingival
overgrowth of periodontal pathogenic bacteria.
Herpesvirus reactivation in periodontal tissue
resulting in transient immunosuppression might
in part explain the episodic progressive nature of
human periodontitis. Tissue tropism in herpesvirus
infection might help explain the localized pattern
of destruction in many cases of periodontitis.
Absence of periodontal herpesvirus infection or
reactivation could allow for some individuals
carrying periodontopathic bacteria in their sub-
gingival microbiota while maintaining periodontal
health.
If some types of destructive periodontal disease
are indeed the result of a herpesvirus-mediated
opportunistic bacterial infection, a new approach
to preventing and treating periodontitis may focus
on controlling the virus(es) that enable overgrowth
of periodontopathic bacteria. Vaccination against
herpesviruses would then constitute an attractive
approach in periodontal prophylaxis and treat-
ment.
Despite circumstantial evidence of a role of
herpesviruses in destructive periodontal disease, a
cause-and-effect relationship remains to be estab-
lished. Questions remain as to whether active
periodontal HCMV infection gives rise to destruc-
tive periodontal disease or whether destructive
periodontal disease reactivates a latent HCMV
infection. The possible involvement of human
herpesviruses in the etiology and pathogenesis of
destructive periodontal diseases merits further
investigation.
References
1. Roizman B. Herpesviridae. In: Fields BN, Knipe DM,
Howley PM, et al., eds. Fields Virology, 3rd edn. Philadel-
phia: Lippincott-Raven Publishers, 1996:2221±2230.
2. Flaitz CM, Nichols M, Hicks MJ. Herpesviridae-associated
persistent mucocutaneous ulcers in acquired immunode®-
ciency syndrome. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1996;81:433±441.
3. Scully C. New aspects of oral viral diseases. In: Seifert G, ed.
Oral Pathology: actual diagnostic and pronostic aspects.
12 Contreras & Slots
Current Topics in Pathology, vol 90. Berlin: Springer Verlag,
1996:29±96.
4. Amir J, Nussinovitch M, Kleper R, Cohen HA, Varsano I.
Primary herpes simplex type 1 gingivostomatitis in pediatric
personnel. Infection 1997;25:310±313.
5. Smith S, Ross JR, Scully C. An unusual oral complication of
herpes zoster infection. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 1984;57:388±398.
6. Laskaris G. Oral manifestations of infectious diseases. Dent
Clin North Am 1996;40:395±423.
7. Porter SR, Mutlu S, Scully CM. Viral infections affecting
periodontal health. Periodont Clin Invest 1993;15:17±24.
8. Berman S, Jensen J. Cytomegalovirus induced osteomyelitis
in a patient with the acquired immunode®ciency syndrome.
South Med J 1990;83:1231±1232.
9. Ficarra G. Oral ulcerations in patients with HIV infection:
etiology, diagnosis and management. In: Greenspan JS,
Greenspan D, eds. Proceedings of the II International
Workshop on Oral Manifestations of HIV Infection.
Chicago: Quintessence Publishing, 1995:205±217.
10. Flaitz CM, Jin YT, Hicks MJ, Nichols CM, Wang YW, Su
IS. Kaposi's sarcoma associated herpesvirus-like sequences
(KSHV/HHV-8) in oral AIDS-Kaposi's sarcoma: a PCR
and clinicopathologic study. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1997;83:259±264.
11. Scully C, Epstein J, Porter S, Cox M. Viruses and chronic
disorders involving the human oral mucosa. Oral Surg Oral
Med Oral Pathol 1991;72:537±544.
12. Parra B, Slots J. Detection of human viruses in periodontal
pockets using polymerase chain reaction. Oral Microbiol
Immunol 1996;11:289±293.
13. Contreras A, Slots J. Mammalian viruses in human
periodontitis. Oral Microbiol Immunol 1996;11:381±386.
14. Banks T, Rouse B. Herpesviruses-immune escape artist?
Clin Infect Dis 1992;14:933±941.
15. Ahmed R, Morrison LA, Knipe DM. Persistence of
viruses. In: Fields BN, Knipe DM, Howley PM, eds.
Fields Virology, 3rd edn. Philadelphia: Lippincott-Raven
Publishers, 1996:219±250.
16. Weir JP. Genomic organization and evolution of the
human herpesviruses. Virus Genes 1998;16:85±93.
17. Millar EP, Troulis MJ. Herpes zoster of the trigeminal
nerve: the dentist's role in diagnosis and management.
J Can Dent Assoc 1994;60:450±453.
18. Purtilo DT. Immunopathology of infectious mononucleosis
and other complications of Epstein±Barr virus infections.
In: Sommers SC, Rosen PP, eds. Pathology Annual, part 1,
vol 15. New York: Appleton-Centrum Crofts, 1980:253±
299.
19. Klein G. Viral latency and transformation: the strategy of
Epstein±Barr virus. Cell 1989;58:5±8.
20. Kieff E. Epstein±Barr virus and its replication. In: Fields
BN, Knipe DM, Howley PM, eds. Fields Virology,
3rd edn. Philadelphia: Lippincott-Raven Publishers,
1996:2343±2396.
21. Rickinson AB, Kieff E. Epstein±Barr virus. In: Fields BN,
Knipe DM, Howley PM, eds. Fields Virology, 3rd edn.
Philadelphia: Lippincott-Raven Publishers, 1996:2397±
2446.
22. Mocarski ES, Stinski MF. Persistence of cytomegalovirus
in human cells. J Virol 1979;31:761±765.
23. Myerson D, Hackman RC, Nelson JA, Ward DC,
McDougall JK. Widespread presence of histologically
occult cytomegalovirus. Hum Pathol 1984;15:430±439.
24. Drew WL. Herpesviridae: Cytomegalovirus. In: Balows A,
Hausler WJ Jr, Lennette EH, eds. Laboratory diagnosis of
Infectious Diseases. Principles and practice. New York:
Springer-Verlag, 1988:247±260.
25. Grundy JE. Virologic and pathogenetic aspects of cyto-
megalovirus infection. Rev Infect Dis 1990;12 (suppl
7):S711±S719.
26. Britt WJ, Alford CA. Cytomegalovirus. In: Fields BN,
Knipe DM, Howley PM, eds. Fields Virology, 3rd edn.
Philadelphia: Lippincott-Raven Publishers, 1996:2493±
2523.
27. Mocarski ED Jr. Cytomegaloviruses and their replication.
In: Fields BN, Knipe DM, Howley PM, eds. Fields
Virology, 3rd edn. Philadelphia: Lippincott-Raven Pub-
lishers, 1996:2447±2492.
28. Sinzger C, Jahn G. Human cytomegalovirus cell tropism
and pathogenesis. Intervirology 1996;39:302±319.
29. Contreras A, Zadeh HH, Nowzari H, Slots J. Herpesvirus
infection of in¯ammatory cells in human periodontitis.
Oral Microbiol Immunol 1999;14:206±212.
30. Lusso P, Markham PD, Tschachler E, et al. In vitro cellular
tropism of human B-lymphotropic virus (human herpes-
virus-6). J Exp Med 1988;167:1659±1670.
31. Braun DK, Dominguez G, Pellet PE. Human herpesvirus-
6. Clin Microbiol Rev 1997;10:521±567.
32. Levy JA. Three new human herpesviruses (HHV-6, 7, and
8). Lancet 1997;349:558±563.
33. Frenkel N, Schirmer EC, Wyatt LS, et al. Isolation of a new
herpesvirus from human CD4z T cells. Proc Natl Acad Sci
USA 1990;87:748±752.
34. DiLuca D, Mirandola P, Ravaoli T, et al. Human
herpesvirus 6 and 7 in salivary glands and shedding in
saliva of healthy and immunode®ciency virus-positive
individuals. J Med Virol 1995;45:462±468.
35. Moore PS, Chang Y. Detection of herpesvirus-like DNA
sequence in Kaposi's sarcoma in patients with and those
without HIV infection. N Engl J Med 1995;322:1181±1185.
36. Chang Y, Moore PS. Kaposi's sarcoma (KS)-associated
herpesvirus and its role in KS. Infect Agents Dis 1996;
5:215±222.
37. Tyler KL, Fields BN. Pathogenesis of viral infections. In:
Fields BN, Knipe DM, Howley PM, eds. Fields Virology,
3rd edn. Philadelphia: Lippincott-Raven Publishers, 1996:
173±218.
38. Epstein JB, Scully C. Herpes simplex virus in immuno-
compromised patients: growing evidence of drug resis-
tance. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
1991;72:47±50.
39. Chee MS, Bankier AT, Beck S, et al. Analysis of the
protein-coding content of the sequence of human cytome-
galovirus strain AD169. Curr Topics Microbiol Immunol
1990;154:125±169.
40. Davison AJ, Scott JE. The complete DNA sequence of
varicella-zoster virus. J Gen Virol 1986;64:1759±1816.
41. Davison AJ, Taylor P. Genetic relations between varicella-
zoster virus and Epstein±Barr virus. J Gen Virol
1987;68:1067±1079.
42. Honess RW. Herpes simplex and the herpes simplex
complex: diverse observations and a unifying hypothesis.
J Gen Virol 1984;65:2077±2107.
43. Challberg MD. A method for identifying the viral genes
required for herpesvirus DNA replication. Proc Natl Acad
Sci USA 1986;83:9094±9098.
44. Wu CA, Nelson NJ, McGeoch DJ, Challberg MD.
Identi®cation of herpes simplex virus type 1 genes required
for origin-dependent DNA synthesis. J Virol 1988;62:435±
443.
45. Gompels UA, Nicholas J, Lawrence G, et al. The DNA
sequence of human herpesvirus-6:structure, coding con-
tent, and genome evolution. Virology 1995;209:29±51.
46. Littler E, Stuart AD, Chee MS. Human cytomegalovirus
VL97 open reading frame encodes a protein that

phosphorylates the antiviral nucleoside analogue ganciclo-
vir. Nature 1992;358:160±162.
47. Steiner I, Kennedy PG. Herpes simplex virus latent
infection in the nervous system. J Neurovirol 1995;1:19±29.
48. Roizman B, Sears AE. Herpes simplex viruses and their
replication. In: Fields BN, Knipe DM, Howley PM, eds.
Fields Virology, 3rd edn. Philadelphia: Lippincott-Raven
Publishers, 1996:2231±2295.
49. Guinan ME, Wolinsky SM, Reichman RC. Epidemiology
of genital herpes simplex virus infection. Epidemiol Rev
1985;7:127±146.
50. Scott DA, Coulter WA, Biagoni PA, O'Neill H, Lamey PJ.
Detection of herpes simplex type 1 shedding in the oral
cavity by polymerase chain reaction and enzyme-linked
immunosorbent assay at the prodromal stage of recrude-
cent herpes labialis. J Oral Pathol Med 1997;26:305±309.
51. Overall JC. Dermatologic viral disease. In: Gallasso GJ,
Merigan TC, Buchanan RA, eds. Antiviral Agents and
Viral Disease of Man, 2nd edn. New York: Raven Press,
1984:247±312.
52. Tateishi K, Toh Y, Minagawa H, Thashiro H. Detection of
herpes simplex virus (HSV) in the saliva from 1000 oral
surgery outpatients by the polymerase chain reaction
(PCR) and virus isolation. J Oral Pathol Med
1994;23:80±84.
53. Eversole LR. Cause of ulcers in HIV-infected patients: a
study of 19 cases. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1996;82:166±172.
54. Miller CS. Viral infections in the immunocompromised
patient. Dermatol Clin 1996;14:225±241.
55. Melbye M, Grossman RJ, Goedert JJ, Eyster ME, Biggar
RJ. Risk of AIDS after herpes zoster. Lancet 1987;1:728±
731.
56. Muto T, Tsuchiya H, Sato K, Kanazawa M. Tooth
exfoliation and necrosis of the mandible. A rare complica-
tion following trigeminal herpes zoster. J Oral Maxillofac
Surg 1990;48:1000±1003.
57. Harding CV. Blastomycosis and opportunistic infections in
patients with acquired immunode®ciency syndrome. Arch
Pathol Lab Med 1991;115:1133±1136.
58. Veenstra J, van Praag RM, Krol A, et al. Complications of
varicella zoster virus reactivation in HIV-infected homo-
sexual men. Acquir Immun Def Synd 1996;10:393±399.
59. Gershon AA. Live attenuated varicella vaccine: protection
in healthy adults compared with leukaemic children.
National Institute of Allergy and Infectious Diseases,
Varicella Vaccine Collaborative Study Group. J Infect Dis
1990;161:661±666.
60. Sixbey JW, Nedrud JG, Raab-Traub N, Hanes RA, Pagano
JS. Epstein±Barr virus replication in oropharyngeal
epithelial cells. N Engl J Med 1984;310:1225±1230.
61. Khanna R, Borrows SR, Moss DJ. Immune regulation in
Epstein±Barr virus-associated diseases. Microbiol Rev
1995;59:387±405.
62. Greenspan JS, Greenspan D, Lennette E, et al. Replication
of Epstein±Barr virus within the epithelial cell of oral
``hairy'' leukoplakia, an AIDS-associated lesion. N Engl J
Med 1985;313:1564±1571.
63. Sculley TB, Apolloni A, Hurren L, Moss DJ, Cooper DA.
Coinfection with A and B type Epstein±Barr virus in
human immunode®ciency virus-positive subjects. J Infect
Dis 1990;162:643±648.
64. Diaz-Mitoma F, Ruiz A, Flowerdew G, et al. High levels of
Epstein±Barr virus in the oropharynx: a predictor of
disease progression in human immunode®ciency virus
infection. J Med Virol 1990;31:69±75.
65. Ficarra G, Barone R, Gaglioti D. Oral hairy leukoplakia
among HIV positive intravenous drug abusers: a clinico-
Herpesviruses in periodontitis 13
pathologic and ultrastructural study. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 1988;65:421±426.
66. Greenspan D, Greenspan JS, DeSouza YG, Levy JA,
Ungar AM. Oral hairy leukoplakia in a HIV-negative renal
transplant recipient. J Oral Pathol Med 1989;18:32±34.
67. Levy JA, Ungar AM. Oral hairy leukoplakia in an HIV-
negative renal transplant recipient. J Oral Pathol Med
1989;18:32±34.
68. Green TL, Greenspan JS, Greenspan D, DeSouza YG.
Oral lesions mimicking hairy leukoplakia: a diagnostic
dilemma. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 1989;67:422±426.
69. Tao Q, Ho FC, Loke SL, Srivastava G. Epstein±Barr virus
is located in tumor cells of nasal lymphomas of NK, T or B
cell type. Int J Cancer 1995;60:315±320.
70. Boulter A, Johnson NW, Birnbaum W, Teo CG. Epstein±
Barr virus (EBV) associated lesions of the head and neck.
Oral Dis 1996;2:117±224.
71. Raab-Traub N, Rajadurai P, Flynn K, Lanier A. Epstein±
Barr virus infection in carcinoma of the salivary gland.
J Virol 1991;65:7032±7036.
72. Brahim JS, Katz RW, Roberts MW. Non-Hodgkin's
lymphoma of the hard palate mucosa and buccal gingiva
associated with AIDS. J Oral Maxillofac Surg 1988;46:328±
330.
73. Colmenero C, Gamallo G, Pintado V, Patron M, Sierra J,
Valencia E. AIDS related lymphoma of the oral cavity. Int
J Oral Maxillofac Surg 1991;20:2±6.
74. Kaugars GE, Burns JC. Non-Hodgkin's lymphoma of the
oral cavity associated with AIDS. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1989;67:433±436.
75. Langford A, Dienemann D, Schuman D, et al. Oral
manifestations of AIDS-associated non-Hodgkin's lym-
phomas. Int J Oral Maxillofac Surg 1991;20:136±141.
76. Vilde JL, Perronne C, Huchon A, et al. Association of
Epstein±Barr virus with lethal midline granuloma. N Engl J
Med 1985;313:1161±1164.
77. Harabuchi Y, Yamanaka N, Katura A, et al. Epstein±Barr
virus in nasal T-cell lymphomas in patients with lethal
midline granulomas. Lancet 1990;335:128±130.
78. Grefte A, Blom N, van der Giessen M, van Son WJ, The
TH. Ultrastructural analysis of circulating cytomegalic cells
in patients with active cytomegalovirus infection: evidence
for virus production and endothelial origin. J Infect Dis
1993;168:1110±1118.
79. Dal Monte P, Lazzarotto T, Ripalti A, Landini MP.
Human cytomegalovirus infection: A complex diagnostic
problem in which molecular biology has induced a rapid
evolution. Intervirology 1996;39:193±203.
80. Spector SA. Hirata KK, Neuman TR. Identi®cation of
multiple cytomegalovirus strains in homosexual men
with acquired immunode®ciency syndrome. J Infect Dis
1984;150:953±956.
81. Ho WZ, Harouse JM, Rando RF, Gonczol E, Srinivasan A,
Plotkin SA. Reciprocal enhancement of gene expression
and viral replication between human cytomegalovirus and
human immunode®ciency virus type 1. J Gen Virol
1990;71:97±103.
82. Schubert MM, Epstein JB, Lloyd ME, Cooney E. Oral
infections due to cytomegalovirus in immunocompromised
patients. J Oral Pathol Med 1993;22:268±273.
83. Greenberg M, Dubin G, Stewart JC, Cumming CG,
MacGregor RR, Friedman HM. Relationship of oral
disease to the presence of cytomegalovirus DNA in
saliva of AIDS patients. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 1995;79:175±179.
84. Glick M, Cleveland DB, Salzin LM, Alfaro Miranda M,
Fielding AF. Intraoral cytomegalovirus lesions an HIV-
14 Contreras & Slots
associated periodontitis in a patient with acquired immu-
node®ciency syndrome. Oral Surg Oral Med Oral Pathol
1991;72:716±720.
85. Dood 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 immunode®ciency virus. J Clin Periodontol
1993;20:282±285.
86. Epstein JB, Sherlock CH, Wolber RA. Cytomegalovirus-
induced gingivitis. Ann Intern Med 1992;116:1034.
87. Salahuddin SZ, Ablashi DV, Markham PD, et al. Isolation
of a new virus, HBLV in patients with lymphoproliferative
disorders. Science 1986;234:596±601.
88. Steeper TA, Horwitz CA, Ablashi DV, et al. The spectrum
of clinical and laboratory ®ndings resulting from human
herpesvirus-6 (HHV-6) in patients with mononucleosis like
illnesses not resulting from Epstein±Barr virus or cytome-
galovirus. Am J Clin Pathol 1990;93:776±783.
89. Kimberlin DW. Human herpesvirus 6 and 7: identi®cation
of a newly recognized viral pathogens and their association
with human disease. Pediatr Infect Dis J 1998;17:59±68.
90. Yadav M, Arivanathan M, Chandrashekran A, Tan BS,
Hashim BY. Human herpesvirus- 6 (HHV-6) DNA and
virus-encoded antigen in oral lesions. J Oral Pathol Med
1997;26:393±401.
91. Contreras A, Nowzari H, Slots J. Herpesviruses in
periodontal pocket and gingival biopsy samples. Oral
Microbiol Immunol 2000;15:15±18.
92. Lusso P, De Maria A, Malnati M, et al. Induction of CD4
and susceptibility to HIV-1 infection in human CD8z T
lymphocytes by human herpesvirus 6. Nature 1991;349:533±
535.
93. Bertram G, Dreiner N, Kreuger GR, et al. Frequent double
infection with Epstein±Barr virus and human herpesvirus-6
in patients with acute infectious mononucleosis. In Vivo
1991;5:271±279.
94. Yoshikawa T, Nakashima T, Suga S, et al. Human
herpesvirus-6 DNA in cerebrospinal ¯uid of a child with
exanthem subitum and meningoencephalitis. Pediatrics
1992;89:888±890.
95. Wilborn F, Schmidt CA, Brinkmann V, Jendroska K,
Oettle H, Siegert W. A potential role for human
herpesvirus type 6 in nervous system disease. J Neuroim-
munol 1994;49:213±214.
96. Luppi M, Barozzi P, Maiorana A, Marasca R, Torelli G.
Human herpesvirus 6 infection in normal human brain
tissue. J Infect Dis 1994;169:943±944.
97. Challoner PB, Smith KT, Parker JD, et al. Plaque-
associated expression of human herpesvirus 6 in multiple
sclerosis. Proc Natl Acad Sci USA 1995;92:7440±7444.
98. Takahashi Y, Yamada M, Nakamura J, et al. Transmission
of herpesvirus 7 through multigenerational families in the
same household. Pediatr Infect Dis J 1997;16:975±978.
99. Sada E, Yasukawa M, Ito C, et al. Detection of human
herpesvirus 6 and human herpesvirus 7 in the submandib-
ular gland, parotid gland and lip salivary gland by PCR. J
Clin Microbiol 1996;34:2320±2321.
100. Nakagawa N, Mukai T, Sakamoto J, et al. Antigenic
analysis of human herpesvirus 7 (HHV-7) and HHV-6
using immune sera and monoclonal antibodies against
HHV-7. J Gen Virol 1997;78:1131±1137.
101. Drago F, Ranieri E, Malagiti F, Losi E, Rebora A.
Human herpesvirus-7 in pityriasis rosea. Lancet
1997;349:1367±1368.
102. Vidimos AT, Camisa C. Tongue and cheek: oral lesions in
pityriasis rosea. Cutis 1992;50:276±280.
103. Kemeny L, Gyulai R, Kiss M, Magy F, Dobozy A.
Kaposi's sarcoma-associated herpesvirus/human herpes-
virus-8: a new virus in human pathology. J Am Acad
Dermatol 1997;37:107±113.
104. Lennette ET, Blackbourn DJ, Levy JA. Antibodies to
human herpesvirus type 8 in the general population and in
kaposi's sarcoma patients. Lancet 1996;348:858±861.
105. Gaspari AA, Marchese S, Powell D, Rady PL, Tyring SK.
Identi®cation of HHV-8 in the skin lesions of Kaposi's
sarcoma in an immunosuppressed patient with bullous
pemphigoid. J Am Acad Dermatol 1997;37:843±847.
106. Di Alberti L, Teo CG, Porter S, Zakrzewska J, Scully C.
Kaposi's sarcoma herpesvirus in oral Kaposi's sarcoma.
Eur J Cancer 1996;32:68±69.
107. Sabiston CB Jr. A review and proposal for etiology of
acute necrotizing gingivitis. J Clin Periodontol 1986;
13:727±734.
108. Sheiham A. An epidemiological survey of acute ulcerative
gingivitis in Nigerians. Arch Oral Biol 1966;11:937±942.
109. Jimenez M, Baer PN. Necrotizing ulcerative gingivitis
in children: a 9 year clinical study. J Periodontol 1975;
46:715±720.
110. Burghelea B, Serb H. Ultrastructural evidence of a
papova-type viral morphogenesis phenomenon in in®l-
trating cells from juvenile periodontal lesions. A case
report. Arch Roum Path Exp Microbiol 1993;64:474±484.
111. Burghelea B, Serb H. Nuclear bodies and virus-like
particles in gingival tissue of periodontopathic patients.
Arch Roum Path Exp Microbiol 1990;49:89±92.
112. Ting M, Contreras A, Slots J. Herpesviruses in localized
juvenile periodontitis. J Periodont Res 2000;35:17±25.
113. Contreras A. Herpes simplex virus in saliva from
advanced adult periodontitis cases: a viral culturing
study. Thesis, Cali, Colombia: Universidad del Valle 1994.
114. Kondo KY, Hakayawa H, Mori S, et al. Detection by
polymerase chain reaction ampli®cation of human herpes
virus 6 DNA in peripheral blood of patients with
examthem subitum. J Clin Microbiol 1990;28:970±974.
115. Kidd MI, Clark DA, Ait-Khaled M, Grif®ths PD, Emery
VC. Measurement of human herpesvirus 7 load in
peripheral blood and saliva of healthy subjects by
quantivative polymerase chain reaction. J Infect Dis
1966;17:396±401.
116. O'Neill E, Henson TH, Ghorbani AJ, Land MA, Webber
BL, Garcia JV. Herpesvirus-like sequences are speci®-
cally found in Kaposi sarcoma lesions. J Clin Pathol
1966;49:306±308.
117. Contreras A, Slots J. Active cytomegalovirus infection
in human periodontitis. Oral Microbiol Immunol 1998;
13:225±230.
118. Ronderos M, Michalowicz B, Camara R, Contreras A,
Slots J. Bacterial and viral risk markers for juvenile
periodontitis. J Periodontol, in press.
119. Rams TE, Listgarten MA, Slots J. Utility of radiographic
crestal lamina dura for predicting periodontitis disease
activity. J Clin Periodontol 1994;21:571±576.
120. Preus HR, Olsen I, Namork E. The presence of phage-
infected Actinobacillus actinomycetemcomitans in loca-
lized juvenile periodontitis patients. J Clin Periodontol
1987;14:605±609.
121. Velazco CH, Coelho C, Salazar F, Contreras A, Slots J,
Pacheco JJ. Microbiological features of Papillon±LefeÁvre
syndrome periodontitis. J Clin Periodontol 1999;26:622±
627.
122. Preus HR, Olsen I, Namork E. Association between
bacteriophage-infected Actinobacillus actinomycetemco-
mitans and rapid periodontal destruction. J Clin Period-
ontol 1987;14:245±247.
123. Contreras A, Falkler WA Jr, Enwonwu CO, et al. Human
Herpesviridae in acute necrotizing ulcerative gingivitis in

children in Nigeria. Oral Microbiol Immunol 1997;12:259±
265.
124. Abramson JS, Wheeler GJ. Virus-induced neutrophil
dysfunction: role in the pathogenesis of bacterial infec-
tions. Pediatr Infect Dis 1994;13:643±652.
125. Bakaletz LO. Viral potentiation of bacterial superinfec-
tion of the respiratory tract. Trends Microbiol 1995;3:110±
114.
126. Bale JF, O'Neil ME, Grenier T. The interaction of murine
cytomegalovirus with murine neutrophils: effect on
migratory and phagocytic activities. J Leuk Biol
1985;38:723±734.
127. Contreras A, Umeda M, Chen C, Bakker I, Morrison JL,
Slots J. Relationship between herpesviruses and adult
periodontitis and periodontopathic bacteria. J Period-
ontol 1999;70:478±484.
128. Smith MacDonald E, Nowzari H, Contreras A, Flynn J,
Morrison JL, Slots J. Clinical and microbiological
evaluation of a bioabsorbable and a nonresorbable barrier
membrane in the treatment of periodontal intraosseous
lesions. J Periodontol 1998;69:445±453.
129. Gerna G, Zipeto D, Percivalle E, et al. Human
cytomegalovirus infection of the major leukocyte sub-
populations and evidence for initial viral replication in
polymorphonuclear leukocytes from viremic patients.
J Infect Dis 1992;166:1236±1264.
130. Fauci AS. Immunopathogenesis of HIV infection.
J Acquir Immun Def Synd 1993;6:655±662.
131. Ruddle NH, Li CB, Horne WC, et al. Mice transgenic for
HTLV-I LTR-Tax exhibit tax expression in bone, skeletal
alterations and high bone turnover. Virology 1993;
197:196±204.
132. Rubin RH. Impact of cytomegalovirus infection on organ
transplant recipients. Rev Infect Dis 1990;12(suppl
7):S754±S766.
133. Carney WP, Rubin RH, Hoffman RA, Hansen WP,
Healey K, Hirch MS. Analysis of T lymphocyte subsets
in cytomegalovirus mononucleosis. J Immunol 1981;
126:2114±2116.
134. Dankner WM, McCutchan JA, Richman DD, Hirata K,
Spector SA. Localization of human cytomegalovirus in
peripheral blood leukocytes by in situ hybridization.
J Infect Dis 1990;161:31±36.
135. Taylor-Wiedeman J, Sissons JGP, Borysiewicz LK,
Sinclair JH. Monocytes are a major site of persistence
of human cytomegalovirus in peripheral blood mono-
nuclear cells. J Gen Virol 1991;72:2059±2064.
136. Fainstein V, Musher DM, Cate TR. Bacterial adherence
to pharyngeal cells during viral infection. J Infect Dis
1980;141:172±176.
137. Chonmaitree T, Owen MJ, Patel JA, Hedgpeth D,
Horlick D, Howie VM. Effects of viral respiratory tract
infection on outcome of acute otitis media. J Pediatr
(St Louis) 1992;120:856±862.
138. Mackowiak PA, Goggans M, Torres W, Dal Nogare A,
Luby JP, Helderman H. Relationship between cyto-
megalovirus and colonization of the oropharynx by
Gram-negative bacilli following renal transplantation.
Epidemiol Infect 1991;107:411±420.
139. Westmoreland D, Watkins JF. The IgG receptor induced
by herpes simplex virus: studies using radioiodinated IgG.
J Gen Virol 1974;24:167±178.
140. Mackowiak PA, Marling-Carson M, Smith JW, Luby JP.
Antibody mediated bacterial adhesion to cytomegalo-
virus-induced Fc receptors. Potential relationship to
secondary infections complicating herpesvirus infections.
J Clin Invest 1984;73:987±991.
141. Patel J, Faden H, Shamara S, Ogra PL. Effect of
Herpesviruses in periodontitis 15
respiratory syncytial virus on adherence, colonization
and immunity of nontypable Haemophilus in¯uenzae:
implications for otitis media. Int J Pediatr Otorhinolar-
yngol 1992;23:15±23.
142. Mutimer D, Mirza D, Shaw J, O'Donnell K, Elias E.
Enhanced cytomegalovirus replication associated with
septic bacterial complications in liver transplant recipi-
ents. Transplantation 1997;63:1411±1415.
143. Klein BS, Dollete FR, Yolken RH. The role of respiratory
syncytial virus and other viral pathogens in acute otitis
media. J Pediatr 1982;101:16±20.
144. Heurlin N, Brattstrom C, Lonnqvist B, et al. Aetiology of
pulmonary diseases in immunocompromised patients. Eur
Respir J 1991;4:10±18.
145. Tosato G, Magrath I, Koski N, Dolley N, Blaese M.
Activation of suppressor-T cells during Epstein±Barr
virus-induced infectious mononucleosis. N Engl J Med
1979;301:1133±1137.
146. Menezes J, Sundar SK, Ahoronheim CA. Immunosup-
presive effects of Epstein±Barr virus infection. In:
Gilmore N, Wainberg MA, eds. Viral Mechanisms of
Immunosuppression. New York: Liss, 1985:115±134.
147. Iwamoto GK, Monick MM, Clark BD, Auron PE, Stinski
MF, Hunninghake GW. Modulation of interleukin 1 beta
gene expression by the immediate early genes of human
cytomegalovirus. J Clin Invest 1990;85:1853±1857.
148. Smith PD, Saini SS, Raffeld M, Manischewitz JF, Wahl
SM. Cytomegalovirus induction of tumor necrosis factor-a
by human monocytes and mucosal macrophages. J Clin
Invest 1992;90:1642±1648.
149. Geist LJ, Monik MM, Stinski MF, Hunninghake GW. The
immediate early genes human cytomegalovirus upregu-
late tumor necrosis factor-a gene expression. J Clin Invest
1994;93:474±478.
150. Taga H, Taga K, Wang F, Chretien J, Tosato G. Human
and viral interleukin-10 in acute Epstein±Barr virus-
induced infectious mononucleosis. J Infect Dis 1995;
171:1347±1350.
151. Whitley RJ. Herpes simplex viruses. In: Fields BN,
Knipe DM, Howley PM, eds. Fields Virology, 3rd edn.
Philadelphia: Lippincott-Raven Publishers, 1996:2297±
2342.
152. Rosen A, Bergeley P, Jondal M, et al. Polyclonal Ig
production after Epstein±Barr virus infection of human
lymphocytes in vitro. Nature 1977;267:52±54.
153. Stashenko P, Dewhirst FE, Peros WJ, Kent RL, Ago MJ.
Synergistic interactions between interleukin 1, tumor
necrosis factor, and lymphotoxin in bone resorption.
J Immunol 1987;138:1464±1468.
154. Gronowicz G, Hadjimichael J, Richards D, Cerami A,
Rossomando EF. Correlation between tumor necrosis
factor-a (TNF-a)-induced cytoskeletal changes and
human collagenase gene induction. J Periodont Res
1992;27:562±568.
155. Gemmell E, Seymour GJ. Modulation of immune
responses to periodontal bacteria. Curr Opin Periodontol
1994;2:28±38.
156. Reynolds JJ, Meikle MC. Mechanisms of conective tissue
destruction. Importance of the balance of metallopro-
teinases and inhibitors in tissue destruction and implica-
tion for human periodontitis and its treatment. Perio-
dontol 2000 1997;14:144±157.
157. Kapasi K, Rice GPA. Cytomegalovirus infection of
peripherical blood mononuclear cells: effects on inter-
leukin-1 and 2 production and responsiveness. J Virol
1988;62:3603±3613.
158. Seymour GJ. Possible mechanisms involved in the
16 Contreras & Slots
immunoregulation of chronic in¯ammatory periodontal
disease. J Dent Res 1987;66:2±9.
159. Goodson J, Tanner AC, Haffajee AD, Sornberger GC,
Socransky SS. Patterns of progression and regression
of advanced periodontal disease. J Clin Periodontol
1982;9:472±481.
160. Seymour GJ, Gemmell R, Reinhart RA, Eastcott J,
Taubman MA. Immunopathogenesis of chronic in¯am-
matory periodontal disease: cellular and molecular
mechanisms. J Periodont Res 1993;28:478±486.
161. Taubman MA, Yoshie H, Ebersole JL, Smith DJ, Olson
CL. Host response in experimental gingivitis disease.
J Dent Res 1984;63:455±460.
162. Stashenko P, Funiyoshi P, Obernesser MS, Prostak L,
Haffajee AD, Socransky SS. Levels of interleukin 1b in
tissue from sites of active periodontal disease. J Clin
Periodontol 1991;18:548±554.
163. Sodek J, Overall CM. Matrix metalloproteinases in
periodontal tissue remodelling. Matrix 1992;1(suppl):
S352±S362.
164. Birkedal-Hansen H. Role of matrix metalloproteinases in
humanperiodontaldiseases.JPeriodontol1993;64:474±484.
165. Gemmell E, Seymour GJ. Cytokines and T cell switching.
Crit Rev Oral Biol Med 1994;5:249±279.
166. Okada H, Kassay Y, Kida T. T lymphocyte subsets in the
in¯amed gingiva of human adult periodontitis. J Perio-
dont Res 1984;19:595±598.
167. CË elenligil H, Kansu E, Ruacan S, Eratalay K, Caglayan G.
Immunohistological analysis of gingival lymphocytes in
adult periodontitis. J Clin Periodontol 1990;17:542±548.
168. CË elenligil H, Ebersole JL. Characteristics and responses
of EBV immortalized B cells from periodontal disease
patients. Oral Dis 1997;3:262±271.
169. Okada H, Kida T, Yamagami H. Identi®cation of
immunocompetent cells in in¯amed gingiva of human
chronic periodontitis. Infect Immun 1983;41:365±374.
170. Seymour GJ, Dockrell HM, Greenspan JS. Enzyme
differentiation of lymphocyte subpopulations in sections
of human lymph node, tonsils and periodontal disease.
Clin Exp Immunol 1978;32:169±178.
171. Mackler BJ, Frostrad KB, Robertson PB, et al. Immu-
noglobulin bearing lymphocytes and plasma cells in
human periodontal disease. J Periodont Res 1977;12:37±
45.
172. Rouse BT, Horohov DW. Immunosuppression in viral
infections. Rev Infect Dis 1989;8:850±873.
173. Schmid DS, Rouse TB. The role of T cell immunity in
control of herpes simplex virus. In: Rouse TB, ed. Herpes
Simplex Virus: pathogenesis, immunobiology and control.
Curr Topics Microbiol Immunol 1992;179:57±74.
174. Rosenstein DI, Eigner TL, Levin MP, Chiodo GT.
Rapidly progressive periodontal disease associated with
HIV infection. J Am Dent Assoc 1989;118:313±314.
175. Lamster IB, Grbic JT, Mitchell-Lewis DA, Begg MD,
Mitchell A. New concepts regarding the pathogenesis of
periodontal disease in HIV infection. Ann Periodontol
1998;3:62±67.
176. Waner JL. Human cytomegalovirus. In: Specter S,
Bendinelli M, Friedman H, eds. Virus-induced Immuno-
suppression. New York: Plenum Press, 1989:101±116.
177. Beersma MF, Bijlmakers MJ, Ploegh HL. Cytomegalo-
virus down-regulates HLA class I expression by reducing
the stability of class I H chains. J Immunol 1993;151:4455±
4464.
178. Howell CL, Miller MJ, Martin WJ. Comparison of rates of
virus isolation from leukocyte populations separated
from blood by conventional and Ficoll-Paque/Macrodex
methods. J Clin Microbiol 1979;10:533±537.
179. Schooley TR, Densen HD, Felsentein D, Hirch MS,
Henle E, Weitzman S. Antineutrophil antibodies in
infectious mononucleosis. Am J Med 1984;76:85±90.
180. Tew JG, Engel D, Mangan D. Polyclonal B-cell activation
in periodontitis. J Periodont Res 1989;24:25±41.
181. Anusaksathien O, Dolby AE. Autoimmunity in perio-
dontal disease. J Oral Pathol Med 1991;20:101±107.