Received: 13 February 2017 | Accepted: 21 April 2017

DOI: 10.1002/jmv.24852

RESEARCH ARTICLE

Increased expression of CD38 and HLADR in HIV-infected

patients with oral lesion

Liliane Lins1 | Érica Farias2 | Clara Brites-Alves2 | Alex Torres2 |

Eduardo M. Netto2 | Carlos Brites1,2

1 School of Medicine, Federal University of

Bahia, Salvador, Bahia, Brazil
2 Research Laboratory of Infectious Diseases,
Edgard Santos Federal University Hospital,
Salvador, Bahia, Brazil
Correspondence
Liliane Lins, School of Medicine, Federal
University of Bahia, Praça XV de Novembro,
Largo do Terreiro de Jesus s/n CEP 400260-
10, Salvador, Bahia, Brasil.
Email: liliane.lins@ufba.br
Persistent immune actiation is associated with innadequate immune recovery in
HIV-patients. This study assessed the relationship between frequency of expression
of cell activation markers (CD38 and HLADR) and presence of oral lesions in HIV-1
infected patients. Fifty-seven HIV-infected persons, undergoing antiretroviral
treatment, were divided into three groups, according to the number of CD4+
T cells and CD4+/CD8+ ratio: adequate, partial, and inadequate immune
restauration. All patients underwent full mouth assessments for saliva flow
measurement, oral mucosal lesion, periodontal disease, and severity of periodontitis.

Funding information
Immune activation markers levels were compared according to three groups of
Brazilian National Research Council (CNPq), periodontal disease (“No periodontal disease,” “gingivitis,” and “periodontitis”). Oral
Grant number: 306885/2011-5
mucosal lesions (P = 0.03) and peridodontal disease (P = 0.03) were associated with
lower CD4+/CD8+ ratio. Patients with oral mucosal lesions had significantly higher
median levels of HLADR and CD38 markers in all T-lymphocytes populations than
patients without oral lesions. Patients with gingivitis and with periodontitis
presented significantly higher median levels of CD3+ HLADR+, CD4+ HLADR+,
CD8+ HLADR+, and CD3+ CD38+ and significantly lower CD4+/CD8+ ratio than
patients with no periodontal disease. Increased levels of HLADR and CD38
expressions in peripheral blood were associated with oral lesions in HIV-positive
patients. Periodontal disease was associated with HLADR expression.

KEYWORDS
activation, human immunodeficiency virus, infection

1 | INTRODUCTION Increased HIV replication is associated with immune activation,

Human immunodeficiency virus (HIV) infection/AIDS represents a
global health problem, especially in less developed countries where
1
lower socioeconomic status may fuel the epidemic. The State of
Bahia, Northeast Brazil presents high rates of social inequality and low
2
life expectancy. The oral health profile of 993 HIV patients from the
HIV State Reference Center revealed that oral lesions were more
frequent among patients with advanced immune suppression (<350
+
CD4 T/viral load > 10 000 copies) and among those with low
schooling level.2
immune cell depletion, immune cell dysfunction, and lymphocyte
turnover. Besides the effects of proinflammatory cytokines and
the direct HIV interaction with different cell types, other infections
may be associated with enhanced cellular activation and promotion of
HIV disease progression.3 Therefore, treating oral infections may help
to slow the evolution of HIV disease.
Not only immunosuppression, as a consequence of CD4+ T cells
depletion, predisposes the individual to periodontal disease.4 It has been
shown that oral bacteria such as F. nucleatum and P. gingivalis can
induce HIV reactivation in latently infected cells and may trigger HIV

J Med Virol. 2017;9999:1–6. wileyonlinelibrary.com/journal/jmv © 2017 Wiley Periodicals, Inc. | 1

2 |
replication.5 There is a positive correlation between periodontitis and
+ 6
production of IFN-gamma, IL-2, IL-18, and CD8 T cells in HIV patients.
The increase of CD38 expression on CD4+ and CD8+ T cells and
elevated counts of CD8+ T cells, expressing HLADR and CD38, have
been associated with rapid progression of HIV-1.7 HIV-positive
patients, as compared to HIV-negative ones, have fewer Langerhans
cells and increased expression of HLADR molecules on the gingival
epithelium cells, suggesting that oral gingiva is atypically affected by
inflammation.8 Several factors such as insufficient thymus activity,
residual HIV production, microbial translocation, coinfections, genetic
factors, ongoing HIV replication, CD4+ cells nadir <200 cells/mm3,
gender, and coinfection by hepatitis C virus are associated with
abnormal CD4+/CD8+ ratio in HIV patients.9–13 However, studies
evaluating inadequate immune response (CD4+ <500 cells/mm3) even
after viral suppression and its relationship with oral disease are scarce
in the scientific literature.
This study aims to assess the association between markers of
cellular immune activation (levels of CD3+, CD4+, and CD8+ T cells by
the frequency of expression of cell activation markers CD38 and
HLADR) and presence of oral lesions in patients infected with HIV-1.
2 | M A T E R I A L A N D ME TH O D S
2.1 | Study population
A total of 57 individuals (39 males and 18 females) aged 32-75 years
(mean age: 49.8 years) were recruited from the HIV Clinic of the
Edgard Santos Federal University Hospital, Salvador, Bahia, Brazil.
Patients on antiretroviral treatment (who had undetectable HIV-1
RNA plasma viral load for at least 6 months) assigned to routine
+ +
evaluation of HIV viral load and of CD4 /CD8 cell count were invited
to enter the study and were divided into three groups, according to the
number of CD4+ T cells and CD4+/CD8+ ratio (R). Patients in these
+
groups were classified as: adequate immune response (AR), CD4 >500
+
and R&gt partial immune restauration (PR), CD4 >500 and R < 1 and
inadequate immune restauration (IR), CD4+ <500 and R < 1.9
2.2 | Oral evaluation
All patients enrolled in the study were referred for oral evaluation,
from January to July, 2015. There were no refusals. The World Health
14
Organization criteria for periodontal disease were used. We
performed full mouth assessments to define the severity of
periodontitis, according to the European Association of Dental Public
Health standards.15,16 In addition, we evaluated clinical attachment
loss, probing pocket depth, tooth mobility, and number of decayed/
missing/filled teeth (DMFT index). Besides periodontal disease, we
also assessed mucosal lesion. Stimulated whole saliva production was
measured. All patients chewed a piece of paraffin for a period of 5 min.
Saliva was spat out in a graduated test tube and measured, excluding
17
the formed foam during collection. We classified as normal the
results ranging 1-3 mL/min; results lower than 1 mL/min denoted
reduced flow of saliva.
LINS ET AL.
2.3 | Statistical methods and ethics considerations
Demographical, clinical, and analytical variables were evaluated
by using SPSS, version 18. The Chi-square test was used for
comparing differences in proportions. The Kruskal-Wallis test
was used to evaluate differences between three groups of
independent variables on a continuous dependent variable,
and the Mann-Whitney test was used, subsequently, when
applicable.
The study protocol was approved by Ethical Review Board, School
of Medicine, Federal University of Bahia (protocol number
24688913.1.0000.5577), in accordance with Brazilian National Health
Council Resolution 499/12, as well as the Declaration of Helsinki,
2013.
2.4 | Specimen collection and treatment of samples
Blood samples were collected in sterile tubes containing 4 mL of
ethylenediamine tetraacetic acid (EDTA) and processed for
serological screening (HBV, HCV, HTLV, EBV, CMV, and syphilis).
The flow cytometry analysis was performed on whole blood, both
for the cell count and for measurement of the activation markers.
The counting of T lymphocytes CD4 + and CD8+ was performed by
binding of anti-CD3, anti-CD4, anti-CD8, and anti-CD45 labeled
monoclonal antibodies. To carry out this procedure were used
TruCount tubes (Becton Dickinson). A precise volume of whole
blood (50 μL) of each participant and appropriate antibody
reagent (20 μL), containing CD4 fluorescein isothiocyanate
(FITC)/CD8, phycoerythrin(PE)/CD3, peridinin chlorophyll pro-
tein (PerCP), and anti-CD45 associated with streptavidin (PeCy5)
were added directly to a TruCOUNT Tube. Samples were mixed
and incubated for 15 min in the dark at room temperature (20° to
25°C). After the addition of 450 µL 1X FACS Lysing Solution and
have been incubated for 15 min in the dark at room temperature,
samples were analyzed on the flow cytometer (FACSCalibur/
Becton Dickinson) and the count of the selected cells was
performed.
For analysis of the frequency of cell activation markers (CD38
and HLADR), we used two polystyrene tubes for each sample. In the
first tube, we added 100 µL of whole blood and 3 µL of each
added monoclonal alone (anti-CD38 associated to FITC; anti-CD3
associated to PE, anti-CD4 associated to PerCP, and anti-HLADR
associated to allophycocyanin (APC). In the second tube, we added
100 µL of whole blood and 3 µL monoclonal CD38 associated to
FITC and anti-CD45 associated to PeCy5. Samples were mixed and
incubated for 20 min at room temperature (20° to 25°C). After
adding 1 mL of lysis buffer solution, samples were incubated for
20 min. After the incubation period, three washing cycles with 1 mL
of saline were performed, and samples were centrifuged for 10 min
at 2500 revolutions per minute at a temperature between 20 and
25 °C. Subsequently, 400 µL saline was added to resuspended cells.
Samples were analyzed by using a FACSCalibur cytometer, using
Cellquest software.
LINS ET AL.
| 3

3 | RE SULTS measurement of the activation markers in all 57 patients. Oral mucosal

All 57 patients tested positive to anti-EBV antibodies, and all but one
tested positive for CMV (IR group). Two individuals had positive
serology for HTLV-1 (PR, n =1; IR, n = 1), six were HBV positive (Anti
HBc-positive, AR, n = 4; PR, n = 2), and ten tested positive for HCV
antibodies (all had detectable HCV viremia by PCR, AR, n = 2; PR, n = 5;
IR, n = 3). Main characteristics of patients are described according to
their immune response in Table 1. Periodontal disease and immune
response were not associated with gender, age, or education (P > 0.05).
3.1 | Oral evaluation
Fifty-five (96.5%) out of the 57 patients were partially edentulous and
30 (52.6%), presented reduced salivary flow. Hyposalivation relative
frequencies according to immune response group were: 11.7% (AR),
60.0% (PR), and 80.0% (IR). Among partially edentulous subjects, 4
(7.0%) were completely edentulous in the upper dental arch and
presented denture stomatitis lesions associated with poor hygiene in
their upper denture prosthesis and oral candidiasis.
Oral mucosal lesion was observed in 18 (31.6%) individuals: 10
(17.5%) had ulcers, 3 (5.3%) angular cheilitis, and 5 (8.8%) stomatitis.
Regarding periodontal diseases, 16 (28.1%) had gingivitis, 9 (15.8%)
periodontitis, and 14 (24.6%) had a dental infection with purulent
drainage upon probing. Table 2 shows characteristics of the oral health
profile of the patients’ groups. Periodontal disease was more frequent
in PR (P = 0.008) and IR (P = 0.005) than in the AR group.
3.2 | T lymphocytes immune activation
Expression of immune activation markers was evaluated in patients
with oral mucosal lesion and periodontal disease. We performed
the whole blood flow cytometry analysis for the cell count and
lesions (P = 0.03) and periodontal disease (P = 0.03) were associated to
abnormal CD4+/CD8+ ratio. Patients with oral mucosal lesions
presented significantly higher median levels of HLADR and CD38
markers in all T-lymphocytes populations than patients without oral
lesions (Table 3).
Since three patients were edentulous, periodontal disease was
evaluated in 54 individuals. Immune activation markers levels were
stratified according to three groups of periodontal disease (“No
periodontal disease,” “gingivitis,” and “periodontitis”). The immune
activation markers levels, except for CD4+, CD38+, and CD8+ CD38+,
differed significantly among all groups (Table 4). Subsequent two-by-
two comparisons between immune activation markers levels of groups
“gingivitis” and “periodontitis” showed no statistically significant
differences (P > 0.05).
Both groups of patients with gingivitis or with periodontitis
showed significantly higher levels of HLADR immune activation
markers in all T-lymphocytes subsets. CD38 immune activation marker
levels differed significantly (P < 0.02) between patients from groups
“no periodontal disease” and “gingivitis,” but not in the groups “no
periodontal disease” and “periodontitis.” The CD4+/CD8+ ratio was
significantly lower in patients with gingivitis (P < 0.007) or with
periodontitis (P < 0.007) than in patients with no periodontal disease.
4 | DISCUSSION
In this study, oral lesions were associated with both HLADR and CD38
markers. Patients with periodontal diseases (periodontitis and gingivi-
tis) presented median levels of CD38 higher than patients without
these diseases, but these differences were not statistically significant.
However, the HLADR expression was associated with periodontitis
and gingivitis. These results can be explained by the effect of immune

TABLE 1 Socio-demograhic and frequency of lymphocytes subsets of 57 hiv patients according to immune response pattern
Immune response groupa

Patients’ characteristics Adequate (N = 17) Partial (N = 20) Inadequate (N = 20) P

Male, n (%) 11 (64.7) 12 (60,0) 16 (80.0) 0.367*
Primary school education, n (%) 4 (23.5) 11 (55.0) 8 (40.0) 0.149*
Income ≤2 Minimal Wage, n (%) 17 (100.0) 14 (70.0) 19 (95.0) 0.010*
Daily use of dental floss, n (%) 9 (52.9) 3 (15.0) 5 (25.0) 0.036*
Alcohol consumption, n (%) 10 (58.8) 9 (45.0) 9 (45.0) 0.634*
Cigarette smoking history, n (%) 6 (35.3) 12 (60.0) 13 (65.0) 0.160*
Age, years, median (IQR) 50.0 (47.5-57.5) 49.4 (42.2-58.7) 47.4 (39.7-53.7) 0.234**
+ 3
CD3 , cells/mm , median (IQR) 1451.0 (1097.5-2211.5) 1755.0 (1495.0-2093.2) 1279.5 (871.5-1507.7) 0.002**
CD4+, cells/mm3, median (IQR) 783.0 (589.0-1214,0) 739.0 (611.2-5839.7) 356.5 (301.7-466.2) 0.001**
+ +
CD4 /CD8 ratio, median (IQR) 1.2 (1.1-1.4) 0.7 (0.6-0.8) 0.7 (0.3-0.7) 0.001**
a
Adequate, CD4+ >500 and CD4+/CD8+ ratio > 1.0; Partial, CD4+ >500 and CD4+/CD8+ ratio < 1.0;
Inadequate, CD4+ <500 and CD4+/CD8+ ratio < 1.0; IQR, Interquartile range.
*Pearson Chi-Square.
**Kruskal-Wallis test for overall comparison among groups.
4 | LINS ET AL.

TABLE 2 Description of oral findings in 57 hiv patients on suppressive HAART, according to the immune response pattern
Immune response group

Oral health profile Adequate (N = 17) Partial (N = 20) Inadequate (N = 20) P

Mucosal lesion, n (%) 3 (17.6) 7 (35.0) 8 (40.0) 0.318*
Dental infection, n (%) 0 (0.0) 9 (45.0) 5 (25.0) 0.007*
Periodontal disease
Gingivitis, n (%) 2 (11.8) 6 (30.0) 8 (40.0) 0.032*
Periodontitis, n (%) 0 (0.0) 5 (25.0) 4 (20.0) 0.020*
DMFT Index-mean (SD) 21.0 (6.6) 21.50 (8.1) 21.0 (6.0) 0.637**
Decayed-mean (SD) 1.0 (1.2) 2.0 (3.5) 3.5 (3.5) 0.051**
Missing-mean (SD) 9.0 (6.8) 14.0 (9.4) 12.0 (8.3) 0.988**
Filled-mean (SD) 5.0 (4.6) 3.50 (3.1) 3.0 (5.1) 0.454**

*Pearson Chi-Square.
**Kruskal-Wallis test for overall comparison among groups.

activation decrease in T-cells subsets under Highly Active AntiRetro-
viral Therapy (HAART) and consequent viral suppression on levels of
T cells immune expression. The expression of CD38 and its evolution
was measured quantitatively by flow cytometry in 25 drug-naive
HIV-positive patients who initiated HAART and were followed for
12 months. Immune activation decreased in all T-cell subsets after
successful HAART in those patients, and it did correlate with the ability
to reconstitute CD4+ T cells counts. Although CD38 is expressed on
naive cells, it tends to disappear with cellular maturation stage.18
Our study has also shown the association of oral lesion with low
CD4+/CD8+ ratio (P = 0.03). Another study has showed association
between CD4+ T cell counts and periodontal disease in HIV-infected
patients, independent of HIV stage.19 Immunohistologic evaluation of
gingival biopsies in HIV-positive and HIV-negative patients, presenting
+
with periodontal disease, showed a decrease of CD4 T cells counts
and of CD4+/CD8+ T cells ratio in the gingival connective tissue of HIV
20
positive individuals.
Periodontal disease was associated to HLADR in all lymphocytes
subsets. When considering the HIV immune response groups, only
CD3+ HLADR was significantly associated with periodontal disease in
Partial and Inadequate groups. Oral epithelium cells such as
keratinocytes, Langerhans cells, and intraepithelial lymphocytes may
express increasing of HLADR antigens in HIV-positive patients.8
Expression of HLADR molecules and the numbers of Langerhans cells
were analyzed by immunofluorescence in biopsies taken from inflamed
periodontal sites of positive and negative HIV patients. Both groups of
patients expressed HLADR molecules in keratinocytes of basal layer.
Langerhans cells were decreased and the expression of HLADR
molecules was increased on the surface of keratinocytes in the oral
gingival epithelium of HIV positive patients as compared with HIV
negative ones. The expression of HLADR by keratinocytes is atypical
and indicates activation by inflammatory mediators.8
CCR5 and CXCR4 tropic strains of HIV-1 may produce proviral
DNA sequences in normal oral keratinocytes culture obtained from
healthy HIV individuals. Coculture analyzes have shown that normal
keratinocytes can efficiently convey infectious HIV-1 virions to
T lymphocytes, suggesting oral mucosal cells might contribute to
HIV-1 infection.21 Oral cavity has also been considered as a target for
HIV pathogenesis and may work as a HIV reservoir.22,23 Enhancement
of HIV-1 reactivation in macrophages has been associated with oral
chronic inflammatory disorders caused by gram-negative bacteria.
These findings suggest that chronic oral disease may be a potential risk
modifier for viral replication, systemic immune activation, and AIDS
progression.22

TABLE 3 Frequency of immune activation markers (median and interquartile range) according to the presence of oral lesion in 57 hiv patients on
suppressive HAART
No oral lesion Oral lesion

Immune activation marker Median IQR Median IQR P (Mann-Whitney)

CD3+ HLADR+ 8.22 5.7-15.4 22.09 13.7-32.1 0.001
CD4+ HLADR+ 1.78 1.0-2.4 4.62 2.6-8.4 0.001
CD8+ HLADR+ 6.18 3.9-10.4 17.10 10.4-25.3 0.001
CD3+ CD38+ 1.39 0.8-4.2 4.02 1.9-10.2 0.004
CD4+ CD38+ 0.92 0.5-2.5 2.46 1.5-6.3 0.031
CD8+ CD38+ 0.65 0.2-1.2 1.21 0.8-3.4 0.002
LINS ET AL.
| 5

TABLE 4 Immune activation markers (median and interquartile range) according to periodontal disease (pd) in 54 HIV patients on suppressive
HAART
No PD (N = 29) Gengivitis (N = 16) Periodontitis (N = 9)

Immune activation markers Md IQR Md IQR P* Md IQR P** P***

CD3+ HLADR+ 6.78 5.2-11.9 15.93 9.5-28.6 0.001 21.24 18.6-26.9 0.001 0.001
CD4+ HLADR+ 1.56 1.0-2.3 2.71 1.1-8.1 0.045 3.10 2.6-14.7 0.004 0.010
CD8+ HLADR+ 6.04 3.6-8.6 13.44 6.3-20.9 0.003 18.06 8.8-19.7 0.006 0.002
CD3+ CD38+ 1.29 0.8-4.0 2.69 1.7-7.8 0.021 3.01 1.3-4.9 0.152 0.045
CD4+ CD38+ 0.81 0.5-2.2 2.08 1.0-5.6 0.033 2.09 0.5-3.2 0.457 0.100
CD8+ CD38+ 0.65 0.2-1.2 1.05 0.5-2.4 0.056 1.05 0.3-1.8 0.417 0.149
CD4+/CD8+ ratio 1.01 0.6-1.2 0.62 0.3-0.8 0.007 0.66 0.5-0.7 0.007 0.040

Md, median; IQR, interquartile range.

*Mann-Whitney test Gengivitis vs No PD.
**Mann-Whitney test Periodontitis vs No PD.
***Kruskal-Wallis test for overall comparison among groups.

Dendritic cells from patients with periodontal disease can be
triggered by several oral bacteria and represent a risk for reactivation
of latent HIV in patients managed successfully with HAART.23
Experiments that used HIV-latently infected dendritic cell models of
both promoter activation and HIV reproduction have shown that
microorganisms from oral biofilms and periodontal disease may
activate HIV-latently infected dendritic cells in gingival tissues and
contribute to HIV exacerbation and failure of anti-retroviral therapy.23
Oral bacteria have the capacity to translocate into the systemic
circulation. Chronic oral infections with loss of oral epithelial barriers
integrity may trigger responses in local T cells, macrophages, and
dendritic cells in gingival tissues.24
Biopsies of oral ulcers from patients with Behcet’s syndrome and
recurrent oral ulcers were compared with control oral biopsies. The
results showed the expression of HLADR on keratinocytes membranes
in 13 out of 15 biopsies from patients with Behcet’s syndrome and oral
ulcers (87.0%), as compared with only 1 (7.0%) out of the 15 controls
biopsies. These results suggest that the immunohistological changes in
these oral lesions may enhance the immune response in the epithelium
with a prominent infiltration of CD4+ and CD8+ T cells.25 CD38
activation has already been described in immunological disease of
mucosa such as lichen planus, but literature is very scarce on this
topic.26 Although we did not evaluate the immune markers in patients’
oral epithelium, the frequency of oral lesion was associated with all
lymphocytes subsets analyzed in their peripheral blood. Oral lesion
+ + + + + +
was associated to CD3 CD38 , CD8 CD38 , CD3 HLADR , CD8
HLADR+ (but not to the CD4 subset) of patients in the group with
Inadequate immune response. These results suggest a possible
association of poor immune response in HIV-infected patients under
successful HAART and oral lesion.
HLADR and CD38 oral lesion expressions, as well the HLADR
expression, in patients with periodontal disease, indicate HIV immune
activation, specifically in the IR group. Multifactorial problems, such as
chronic oral inflammatory disorders, can contribute to activation of
HIV-latently infected cells in gingival tissues, as well as viral replication
and AIDS progression. The high levels of immune markers in oral
mucosa may be explained by the loss of oral epithelial barriers integrity
in chronic oral infection that may trigger local immune responses in
local.22
This study has some limitations such as small sample size and non-
probabilistic sample selection. Also, the cross-sectional design limits
the generalization of our findings. However, the use of three well
defined groups of patients, with different patterns of immune
restauration, and long-term viral suppression allow us a better
understanding of the relationships between these factors.
Our study demonstrated the association of increased levels of
HLADR and CD38 expressions in peripheral blood in HIV-positive
patients with oral lesions. Periodontal disease was associated with
HLADR expression in HIV-infected patients under antiretroviral
treatment. Taken together, these findings suggest that oral health can
significantly impact the immune response in HIV patients, even for those
under suppressive HAART. Further studies are necessary to investigate
the correlation of high levels of HLADR and CD38 not only in peripheral
blood, but also in the oral epithelium of HIV-positive patients.
DISCLOSURES
No competing financial interests exist.
ACKNOWLEDGMENT
+
This work was supported by a Brazilian National Research Council
(CNPq), Grant 306885/2011-5.
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