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* HIV Immunopathogenesis Laboratory, Wistar Institute, and
Children’s Hospital of Philadelphia, Division of Immunologic and Infectious Diseases, Philadelphia, PA 19104;
Philadelphia Field Initiation Group for HIV Trials, Philadelphia, PA 19103; and
Laboratory for Immunological Research, Schering-Plough, Dardilly, France
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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production
(p < 0.0001). The decrease of the PDC subsets did
not correlate with CD4 count or viral load and was not reversed in
subjects under virally suppressive treatment, suggesting an
irreversible change after infection. By contrast, the absolute number
and median frequency of MDC in HIV-infected individuals were similar to
those observed in uninfected controls, while a significant decrease was
present in subjects with >5000 HIV-1 copies/ml. The inverse
association with viral load of the MDC number, but not of IFN-
secretion or the number of PDC, suggests a role for MDC in viral
control. Our data suggest that DC subsets are differentially
reconstituted during the immune recovery associated with antiviral
therapy. The persistent impairment of certain DC subsets may result in
a sustained defect in DC-mediated innate immune functions despite an
effective treatment regimen. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Members of a distinct family of bone marrow-derived cells, DC represent
<1% of total cells in peripheral blood and in lymphoid and some
nonlymphoid tissues (3). In addition to participating in
the regulation of adaptive responses, DC have a direct role in
enhancing innate immune responses by regulating NK and macrophage
functions (4). Recently, at least two distinct human DC
subsets, myeloid DC (MDC) and plasmacytoid DC (PDC), have been
characterized (5, 6, 7, 8). MDC, also referred to as DC1 or APC
type 1 (APC1), express CD11c and CD1c Ags and are associated with Ag
uptake, T cell activation, dendritic morphology, stimulation of MLRs,
and ability to secrete IL-12 in response to bacterial stimuli
(9, 10, 11). PDC, also referred to as lymphoid DC, DC2, APC2,
or IFN--producing cells, express CD123, BDCA-2, and BDCA-4 Ags and
are characterized by a lymphoid morphology, modest Ag-presenting
potential, and high virus-induced IFN- secretion (7, 9, 10, 12, 13). Dysfunction and potential loss of DC subsets in HIV-1
infection could be associated with decreased T cell activation
(Ag-specific or allogeneic responses) and secretion of type 1 cytokines
(e.g., IL-12, IL-15, and IFN-) that may be in part responsible for
the patients’ increased susceptibility to O.I. (14, 15, 16).
A selective loss of IFN- production was associated with impairment
of accessory cell function in HIV infection (16, 17). A
decreased number of MDC was shown in late-stage patients and in primary
HIV-1 infection (18, 19), and more recently loss of PDC,
defined by CD123 expression, was described in patients with high viral
loads or in those with AIDS that develop O.I. or cancer (20, 21) and in primary HIV-1 infection (19). Among the
limited studies that have measured effects of therapy on circulating
peripheral blood DC, viral suppression following monotherapy with AZT
has been associated with an increase in number of MDC and MLR activity
(22), and more recently a moderate increase in PDC after
HAART (19). However, it remains unknown whether DC
functions may be recovered following suppressive HAART and whether the
MDC and PDC subsets are differentially regulated and associated with
viral control in chronically HIV-infected subjects. The recent
availability of new DC markers for MDC and PDC subsets
(23) allows a more accurate detection, quantitation, and
characterization of DC subsets in HIV infection.
To analyze the potential alteration in DC function in circulating blood
during HIV infection, we evaluated phenotypic and biological properties
of two major subsets of DC from a cross-sectional cohort of
HIV-infected donors and uninfected control subjects. Our data show that
MDC number is inversely associated with viral load in untreated chronic
HIV-1-infected patients and increases under HAART, in contrast to a
sustained loss of PDC (CD123+ or
BDCA-2+) subset and a concurrent decrease in
IFN- secretion.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Consenting chronically HIV-seropositive patients (n = 65) at various stages of disease were enrolled in this study. All patients were from the Jonathan Lax Immune Disorder Clinic (Philadelphia Field Initiation Group for HIV Trials). CD4 T cell counts range from 9 to 1,347 (mean of 501 cells/mm3), and viral load from <50 to 199,000 copies/ml (mean of 15,091 copies/ml). Twenty-one patients were not receiving therapy, and 44 were under HAART. Ninety-six percent of virally suppressed patients (viral load <50 copies/ml) were under HAART. None of the patients presented any O.I. or HIV-related neoplasms. Healthy HIV-1-seronegative donors from the Wistar Institute Blood Donor Program were included as control subjects. Institutional Review Board approval (from the Wistar Institute and Philadelphia Field Initiation Group for HIV Trials) and informed consent were obtained before blood donation. Blood was processed within 2–3 h from drawing. All reagents used were selected for their low levels of endotoxin contamination. PBMC were separated on Ficoll-Paque (Amersham Pharmacia Biotech, Uppsala, Sweden) density gradient and resuspended in RPMI 1640 medium supplemented with 10% heat-inactivated FBS, L-glutamine, and antibiotics.
Whole blood phenotypic analysis of MDC and PDC/IFN--producing
cell subsets
A total of 200 µl blood was lysed in ammonium chloride (Pharml; BD PharMingen, San Diego, CA) at room temperature and washed twice in FACS buffer (PBS, 2% FBS, 0.5% BSA, and 0.02% sodium azide). Cell pellets were incubated in 200 µl FACS buffer with adequate amounts of mAb at room temperature for 20 min. The following mAbs were used: lineage mixture (Lin1-FITC), HLA-DR-PerCP, CD123-PE, and CD11c-allophycocyanin or PE, from BD Immunocytometry Systems (San Jose, CA). PE-conjugated BDCA-2 Ab was purchased from Miltenyi Biotec (Auburn, CA). Irrelevant isotype-matched (IgG1, IgG2b) mAbs were used in each experiment. MDC were identified by Lin-HLA-DR+CD11c+ and PDC by Lin-HLA-DR+CD123+ and by the newly described mAb BDCA-2 (HLA-DR+BDCA-2+) that identify a novel human DC Ag on peripheral blood PDC (23). Cells were washed twice with FACS buffer, fixed, and analyzed in a FACSCalibur with CellQuest software (BD Immunocytometry Systems). The fluorescence of 150,000–200,000 events was accumulated for analysis. When indicated, the absolute number of circulating blood DC (MDC and PDC) was calculated using the percentage of cells with respect to the lymphocyte and monocyte absolute counts, as determined by an automated differential blood count.
IFN- production
PBMC (2.5 x 106/well) from controls
and patients were cultured in 24-well plates with irradiated cell-free
viral supernatant (5HA Influenza-PR8 or 105 PFU
HSV-1-NS) for 18 h. As control for Influenza-PR8, allantoid fluid
was used and did not induce any detectable amount of IFN- (data not
shown). Cell-free supernatants were harvested and tested by a
commercial ELISA using matched Ab pair for IFN- and performed
according to the manufacturer (Endogen, Woburn, MA). Absorbance was
measured on an automatic ELISA reader. Sensitivity of the assay was
8–12 pg/ml.
Mixed lymphocyte reaction
MLR was performed as described by Young and Steinman (24). A total of 2 x 105 plastic nonadherent mononuclear cells isolated from the umbilical cord blood of healthy term neonates by Ficoll-Paque density gradient centrifugation was used as responders. Responding cells were cultured in triplicate for 5 days with 1 x 105/well irradiated allogeneic stimulator cells in 96-well plates in 200 µl medium. Cultures were pulsed with [3H]TdR (1 µCi/well; Amersham, Arlington Heights, IL) for 16 h. Nuclei were collected into fiberglass filter paper (Packard Instrument, Meriden, CT). Radioactivity in the filter paper was quantified as cpm by use of a direct beta counter 9600 (Packard Instrument). Results were expressed as stimulation index (SI) determined as follows: mean cpms in cultures containing responding and stimulator cells/mean cpms in culture containing responder cells alone. A SI of 3 and above was considered positive.
Statistical analysis
This was performed with JMP 4.0 software (SAS Institute, Cary, NC). Data were compared using paired or unpaired nonparametric tests, as appropriate. Statistical significance between HIV- and HIV+ was performed by the Wilcoxon tests. Correlation and association between CD4 counts, viral load, and other parameters were performed by the Spearman’s rank test. When needed, patients were stratified according to their CD4 T cell counts (<250, 250–500, >500), viral load (<50 copies/ml, 50–5000 copies/ml, and >5000 copies/ml), and combination antiretroviral therapy. All p values are two sided.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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We analyzed the phenotype and functions of the two major
peripheral blood DC subsets (MDC and PDC) in a cross-sectional cohort
of healthy uninfected controls (n = 53) and chronically
HIV-infected individuals (n = 65). Cells were
quantified by multiparametric flow cytometry on whole blood (Fig. 1
shows a representative analysis). Our
patient cohort consisted of HAART-treated (n = 44) and
untreated individuals (n = 21), with a
CD4+ T cell number ranging from 9 to
1,347/mm3 and a viral load from <50 to 199,000
copies/ml. The median frequency of PDC in control individuals was
0.29% (7,250 cells/ml) for CD123+ subset and
0.37% (8,250 cells/ml) for BDCA-2+ subset,
whereas that of MDC was 0.27% (6,625 cells/ml). PDC were
significantly (p < 0.001) decreased in
patients (0.10%, 3,288 CD123+ cells/ml; 0.09%,
2,612 BDCA-2+ cells/ml) as compared with healthy
controls (Fig. 2 and Table I). The proportions of PDC
(CD123+ and BDCA-2+) were
highly correlated in both control (r = 0.55,
p = 0.007, n = 21) and HIV-infected
subjects (r = 0.64, p < 0.001,
n = 33), indicating that these two phenotypes
(CD123+ and BDCA-2+)
identify largely overlapping cell subsets. Unlike PDC, the median
frequency of MDC in HIV-infected patients (0.27%, 6,100 cells/ml) was
similar to that observed in uninfected controls (0.27%, 6,625
cells/ml; Fig. 2 and Table I). Additional DC subsets analyzed include
the newly described BDCA-3+ subset
(23), which was found to be decreased in patients as
compared with uninfected controls (0.03%, 1,000 cells/ml vs 0.07%,
1,750 cells/ml, p = 0.0034, data not shown). However,
because the nature of the BDCA-3+ subset is still
poorly understood, further functional characterization of this subset
is needed before its role in the context of an immune response can be
interpreted.
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secretion and MLR response as functional correlates of PDC
and MDC subsets
To gain further insight into the functional outcome of the
decrease in circulating PDC, we evaluated the production of IFN- by
healthy uninfected controls (n = 36) and HIV-infected
individuals (n = 48) in response to
Influenza-PR8 or HSV-1-NS strain exposure. IFN- has a potent
antiviral and antitumor activity and, within peripheral blood, it is
selectively produced by PDC following enveloped viral stimulation
(7, 11, 20). Consistent with a decreased number of
circulating PDC in HIV infection, PBMC from HIV-infected patients
produced on average 20-fold less IFN- than PBMC from control donors
when stimulated in vitro with either Influenza-PR8 or HSV-1-NS
(p < 0.0001, Fig. 3). Moreover, a positive correlation was
found between PDC frequencies and IFN- production by PBMC in
response to either virus (Rho = 0.8, p
< 0.0001 for CD123, and Rho = 0.699, p <
0.0001 for BDCA-2, respectively).
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, even
though the PDC compartment was impaired in the HIV-infected patients
(as indicated by their decreased frequency and IFN- secretion), MDC
frequency and the allostimulatory function of PBMC from the patients
were comparable with those of the controls. Moreover, no significant
difference was observed in the MLR assays between virally suppressed
(<50 copies/ml) and viremic patients (>50 copies/ml). Our results,
indicating that MDC from HIV-infected patients are not impaired in
their ability to stimulate allogeneic T cells, are in agreement with
earlier reports (25, 26) and with our previous observation
using enriched population of total DC (27). Interestingly,
we found a positive correlation between the frequency of the MDC subset
and the MLR response (r = 0.70, p = 0.0073)
consistent with a role for the MDC subset in this functional response.
Taken together, these results strongly suggest a dichotomy between PDC
and MDC in our cohort of HIV-infected individuals: the depletion of PDC
is associated with impairment of IFN- production, while MDC are
maintained and retain functional allogeneic responses.
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We compared patients grouped according to CD4 count or viral load,
as described in Materials and Methods, to address the
question of whether the PDC and MDC subsets were affected by CD4 T cell
counts, viral load, or antiretroviral therapy. Statistical anal-ysis
revealed no correlation between CD4 T cell counts or viral load and PDC
frequency (defined by expression of CD123+ or
BDCA-2+), albeit their number in the patients was
significantly decreased in comparison with healthy uninfected controls.
Importantly, analysis of PDC in virally suppressed patients as compared
with uninfected controls revealed a sustained decrease in both cell
frequency and IFN- secretion (Tables II
and III), indicating that the loss of PDC is
not reversed by antiretroviral treatment. IFN- production was
significantly associated with CD4 counts only when the analysis was
restricted to viremic patients with >50 HIV copies/ml (data not
shown). In contrast to a recent report in which increased levels of
IFN- secretion were described following HAART (28),
impaired IFN- production was observed in treated patients with
complete viral suppression (<50 copies/ml) as well as in patients with
persistent viral replication (>50 copies/ml, p <
0.0001 when compared with controls; Table III). The differences in the
results reported in this study and the one mentioned above
(28) could depend on specific characteristics of the
patient cohorts studied: e.g., none of the patients used in this study
had a history of O.I. or oncological diseases. It should also be noted
that our interpretation of a sustained decrease in IFN- secretion
(by ELISA) rests on a direct comparison with uninfected controls, while
the above mentioned study addressed recovery based on
investigator-assigned thresholds of IFN- secretion (by bioassay)
within specific HIV+ populations
(28). Taken together, our results suggest that a loss of
PDC may be an early event in HIV infection with a limited capacity for
reconstitution following antiretroviral therapy, as reflected by
persistent low frequency of PDC in subjects under treatment with <50
HIV copies/ml and high CD4 T cell count.
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0.29%) and only two of these individuals, with CD4
counts of 1246 and 651 cells/mm3, had normal
IFN- responses. These data suggest that retention of the PDC subset
may be possible in a small subset of patients highly responsive to
antiretroviral therapy, as it was previously described for the
long-term nonprogressor patients (20). Additional
experiments isolating the PDC will be needed to determine whether a
decrease in IFN- secretion is due to a decrease in frequency of PDC
or whether a functional impairment of this subset is also present.
Our data confirm a recent report by Feldman et al. (29)
and support the association in HIV-infected patients between a decrease
in IFN- secretion and a decrease in the CD123+
DC subset, and extend it with the use of additional markers such as
BDCA-2.
CD4 counts, viral load, and frequency of MDC
The overall frequency of MDC in patients remained stable with
similar cell percentage as compared with uninfected controls (Fig. 2
and Table I). No correlation was found between MDC frequency and
CD4+ T cell counts (data not shown). However,
virally suppressed patients were found to have a significantly higher
number of MDC (0.31%; 7020 cells/ml) than patients with a viral load
of >5000 copies/ml (0.13%; 2636 cells/ml, p <
0.0032; Table III). An association between a decrease of MDC frequency
with an increase of viral load was further indicated by a significant
negative correlation between these variables (Rho = -0.5,
p < 0.0001, n = 65). The inverse
association between MDC and viral load was also sustained when the
analysis was restricted to a subset of 21 patients not receiving
treatment (Rho = -0.68, p = 0.0007). It is
important to note that the extensive use of antiviral treatment in our
cohort may have biased our study against the possibility to detect the
previously reported decreases in MDC during HIV infection
(18), specifically the prevalence of HIV-infected subjects
with <5000 copies/ml that did not show a significant decrease in MDC
frequency compared with healthy controls. Overall, these results are
consistent with a decreased MDC frequency only at high viral loads that
can be reversed following antiretroviral treatment in contrast to the
early and persistent deficiency in the PDC subset measured in the same
patients, as described above. A longitudinal analysis of the
consequences of HAART-mediated suppression on each DC subset (i.e.,
recovery of number and function as a correlate of viral suppression) is
needed to confirm our cross-sectional findings.
We show for the first time a differential depletion between the
frequency and function of MDC and PDC subsets when analyzed in parallel
under suppressive therapy. Our data complement previous observations
describing the depletion of MDC and PDC in viremic or end-stage
HIV-infected patients (20, 21, 28). However, our studies
indicate a lack of full DC reconstitution upon HAART that may
contribute to a sustained immune impairment in these subjects. While we
document a phenotypic and functional preservation in the MDC subset in
the virally suppressed patients and HAART-responding patients,
alteration in the PDC subset appears to be an early event and
associated with a sustained impairment of IFN- production. The
consequence of the lack of recovery of IFN- production and PDC
number on the innate and adaptive immune functions of the patients
remains to be defined. For example, a decrease in viral-induced IFN-
secretion may also affect in part the immune reconstitution of NK cell
function. Additional experiments should assess whether the loss of this
subset from circulation reflects a cytopathic effect caused by the
virus through direct infection of the PDC subset (30) or
through viral-induced apoptosis, as described with measles virus
infection (31, 32). A role for interactions between HIV-1
and PDC subsets is supported by the susceptibility of
IL-3-cultured
Lin-HLA-DR+CD11c-
cells to be infected in vitro by HIV-1 (30). It is also of
interest to relate our findings to current treatment guidelines for HIV
infection, as a delay in treatment of patients with viral loads above
5000 copies/ml, irrespective of CD4 T cell count, would not prevent a
decrease of MDC and PDC that may bear on immune function in
general.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Luis J. Montaner, HIV Immunopathogenesis Laboratory, Wistar Institute, 3601 Spruce Street, Room 480, Philadelphia, PA 19130. E-mail address: montaner{at}mail.wistar.upenn.edu
3 Abbreviations used in this paper: O.I., opportunistic infection; DC, dendritic cell; HAART, highly active antiretroviral therapy; MDC, myeloid DC; PDC, plasmacytoid DC.
Received for publication January 7, 2002. Accepted for publication February 22, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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J.-P. Herbeuval, A. W. Hardy, A. Boasso, S. A. Anderson, M. J. Dolan, M. Dy, and G. M. Shearer Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: Role of type I IFN-producing plasmacytoid dendritic cells PNAS, September 27, 2005; 102(39): 13974 - 13979. [Abstract] [Full Text] [PDF]
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A. Smed-Sorensen, K. Lore, J. Vasudevan, M. K. Louder, J. Andersson, J. R. Mascola, A.-L. Spetz, and R. A. Koup Differential Susceptibility to Human Immunodeficiency Virus Type 1 Infection of Myeloid and Plasmacytoid Dendritic Cells J. Virol., July 15, 2005; 79(14): 8861 - 8869. [Abstract] [Full Text] [PDF]
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H. Hashizume, T. Horibe, H. Yagi, N. Seo, and M. Takigawa Compartmental Imbalance and Aberrant Immune Function of Blood CD123+ (Plasmacytoid) and CD11c+ (Myeloid) Dendritic Cells in Atopic Dermatitis J. Immunol., February 15, 2005; 174(4): 2396 - 2403. [Abstract] [Full Text] [PDF]
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 D C Baumgart, D Metzke, J Schmitz, A Scheffold, A Sturm, B Wiedenmann, and A U Dignass Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells Gut, February 1, 2005; 54(2): 228 - 236. [Abstract] [Full Text] [PDF]
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K. McKenna, A.-S. Beignon, and N. Bhardwaj Plasmacytoid Dendritic Cells: Linking Innate and Adaptive Immunity J. Virol., January 1, 2005; 79(1): 17 - 27. [Full Text] [PDF]
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