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IMMUNOBIOLOGY
From Unité INSERM 445, Immunologie des
pathologies infectieuses et tumorales, Département
d'Immunologie, Institut Cochin de Génétique
Moléculaire and Laboratoire de Virologie, Hôpital
St-Vincent de Paul, Paris, France; Unité INSERM 292, PRIMO Cohort
Study Group, Equipe INSERM E0109, Immunité antivirale
systémique et cérébrale, and Service de
Médecine Interne, Hôpital de Bicêtre, Le
Kremlin-Bicêtre, France; and Service d'Immuno-Hématologie,
Hôpital St Louis, Paris; France.
Successful immunologic control of HIV infection is achieved only in
rare individuals. Dendritic cells (DCs) are required for specific antigen presentation to naive T lymphocytes and for antiviral, type I interferon secretion. Two major blood DC populations are found:
CD11c+ (myeloid) DCs, which secrete IL-12, and
CD123+ (IL-3-receptor+) DCs (lymphoid), which
secrete type I interferons in response to viral stimuli. The authors
have previously found a decreased proportion of blood
CD11c+ DCs in chronic HIV+ patients. In this
study, 26 to 57 days after infection and before treatment,
CD123+ and CD11c+ DC numbers were dramatically
reduced in 13 HIV+ patients compared with 13 controls
(P = .0002 and P = .001,
respectively). After 6 to 12 months of highly active
antiretroviral therapy, DC subpopulation average numbers remained low,
but CD123+ DC numbers increased again in 5 of 13 patients.
A strong correlation was found between this increase and CD4 T-cell
count increase (P = .0009) and plasma viral load decrease
(P = .009). Reduced DC numbers may participate in the
functional impairment of HIV-specific CD4+ T cells
and be responsible for the low type I interferon responsiveness already
known in HIV infection. The restoration of DC numbers may be
predictive of immune restoration and may be a goal for immunotherapy to
enhance viral control in a larger proportion of patients.
(Blood. 2001;98:3016-3021) Human immunodeficiency virus (HIV) infection is
fought by the immune system with limited success. The primary stage is
critical. During the first days after infection, the virus replicates
to reach high plasma levels, then decreases. CD4+ T
lymphocytes are the main targets of infection. CD4 T-cell counts drop,
then rise again to subnormal levels, and functional proliferative and
T-helper 1 (TH1)-type secretion responses to HIV antigens are
impaired, including interleukin 2 (IL-2) production.1-3
CD8+ T lymphocyte responses are not as high in primary HIV
infection as in other viral infections and are impaired at later stages of disease.1,4-6 After 6 months, the plasma viral load
reaches a set point which is correlated with the probability of
survival, and convergent evidence has shown the crucial role of
HIV-specific CD8+ T cells and CD4+ T-helper
cells.7-9 Highly active antiretroviral therapy (HAART) has
changed the prognosis.10 Under treatment, CD4 cell counts increase again. HIV-specific CD4+ functional response
restoration appears limited,11 but can be obtained when
HAART is initiated very early after acute
infection,1,12,13 and even in chronic infection, after
prolonged periods of viral suppression.14,15
However, if HAART is discontinued, replication flares again within
2 weeks.16
Some exceptional individuals seem to control the virus after treatment
interruption.17 The immune system also seems to control HIV infection successfully in rare long-term
nonprogressors18,19 and in exposed, noninfected
individuals who have anti-HIV CD8+ T
lymphocytes.8,20,21 Because there is a clear role for the
immune system in viral replication control, defects in
antigen-presenting cells (APCs) may be crucial.
Among APCs, dendritic cells (DCs) are the only cells that can stimulate
naive T lymphocytes.22 In peripheral blood, they are
mostly immature and comprise 2 major populations. "Myeloid" DCs
express CD11c and other myeloid-related surface molecules, including
the granulocyte macrophage colony stimulating factor (GM-CSF) receptor.
They are dependent on GM-CSF for growth and survival. When stimulated,
they secrete IL-12, a key cytokine for the induction of cytotoxicity
and TH1-type secretions by T lymphocytes. "Lymphoid" DCs do not
express CD11c, but the IL-3 receptor, and are dependent on IL-3 for
survival.23,24 Importantly, they are responsible for type
I interferon (IFN) secretion in response to viral
stimuli.25,26
DCs can be infected by HIV in vitro and in vivo, although with a low
frequency,27 and mediate CD4+ T-cell
transinfection.28 Because they are the only APCs that can
stimulate naive T lymphocytes, they are required for vaccination and
induction of primary immune responses at the onset of infection and
immune responses against variant epitopes. DCs are also agents of
innate immune responses to viruses, through type I IFN
secretion25,26,29 and natural killer (NK) cell
activation.30 Therefore, DC defects in HIV infection would
decrease innate and adaptative immune responses against the virus.
Impairment of antigen presentation was found in HIV infection,
particularly a defect in alloantigen presentation by Langerhans cells In the present work, we investigated whether CD123+ DCs
were also decreased in HIV infection. We studied both DC subpopulations during the primary infection, when therapeutic intervention appears to
have the greatest impact on establishment of the balance between the
virus and the immune system. In addition, we determined whether early
initiation of HAART would affect DCs, by quantifying them longitudinally before treatment initiation and after 6 to 12 months of treatment.
Patients and controls
Flow cytometry
Statistical analysis
Type I interferon plasma level assay IFN titrations were performed using a biologic assay.36 Plasma was diluted 2-fold in duplicate in 96-well microplates. Madin Darby bovine kidney (MDBK) cells, which are sensitive to type I but not type II IFNs, were added in 10% FCS minimum essential medium (MEM) (30 000/100 µL per well). Mixtures were incubated at 37°C for 18 hours then vesicular stomatitis virus was added (multiplicity of infection: 1). Cytopathic effect was scored under the microscope 24 hours later. Titration end points represent dilutions that gave destruction of 50% of the cells. A laboratory reference of human IFN-alpha, standardized with the National Institutes of Health (NIH) Ga 023-902-530, was included with each titration. In addition, antiviral activity was further characterized by neutralization with IFN-alpha-specific antiserum.
CD123+ and CD11c+ DC numbers are decreased during HIV primary infection Thirteen HIV+ patients were studied 26 to 57 days after the estimated date of infection, then after 6 to 12 months of HAART (Table 1). They had on average 620 ± 230 CD4 T lymphocytes/µL (median 600, range, 194-954) and 5.4 ± 1.2 logs viral RNA copies/mL plasma (median 5.3, range 2.6-7.1). The numbers of CD123+ (lymphoid) and CD11c+ (myeloid) DCs were assessed by flow cytometry using rare event analysis33-35 (Figure 1). The R1 gate containing PBMCs and excluding debris and polynuclear cells (Figure 1A) was combined with an R2 gate excluding cells strongly positive for other lineage-specific molecules (T and B lymphocytes, monocytes, natural killer [NK] cells, Figure 1B). Some weakly positive lineage cells were retained in gate R2, because they comprised intricated populations of myeloid DCs (HLA-DR++, CD14low, CD11c+) and of monocyte/macrophages (HLA-DR+, CD14low; 4-color labeling, data not shown). Therefore, the HLA-DR+, Lin quadrant
(Figure 1B) contained lymphoid DCs, myeloid DCs, and monocyte/macrophages mostly represented in the lower right corner of
this quadrant but difficult to separate from the myeloid DCs in this
plot. However, they could be separated after further labeling with
CD11c, since myeloid DCs are HLA-DR++, CD11c+
(Figure 1C, gate R4), whereas monocyte/macrophages are
HLA-DR+, CD11c+ (Figure 1C, under gate R4).
Lymphoid DCs were delineated as HLA-DR+, CD123+
in gate R3 (Figure 1D); they expressed HLA-DR less strongly than myeloid DCs (4-color labeling, data not shown).
Figure 2 shows data from a representative
control donor and a representative HIV+ patient. In the
patient, a low proportion of CD123+ DCs (0.13% of PBMCs vs
0.50% in the control) and of CD11c+ DCs (0.22% vs 0.55%)
was found before treatment initiation. These proportions were typical
of the whole patient group (Table 2, Figure 3). Indeed, the mean number of
CD123+ DCs was greatly decreased in the patients compared
with 13 healthy donors (4320/mL ± 2510/mL vs 12 300/mL ± 6500/mL
blood, P = .0002). The numbers of CD11c+ DCs
were also decreased in the patients (5590/mL ± 3050/mL blood) compared with the controls (16 900/mL ± 14 300/mL blood,
P = .001). In fact, in 8 of 13 patients, the
CD11c+ DC subpopulation became difficult to distinguish
from other mononuclear, lineage-weak or lineage-negative
cells expressing HLA-DR and CD11c (Figure 2). No correlation
was found between DC numbers and CD4+ T-lymphocyte counts
or viral load before treatment initiation. Therefore, the numbers of
blood CD123+ as well as CD11c+ DCs were clearly
decreased in these patients during primary infection.
CD123+ blood DC number recovery under HAART correlates with CD4 count increase and viral load decrease HAART, administered for 6 to 12 months, induced at least a 2-log decrease in plasma viral load in 11 of 13 patients, reaching undetectable levels (1.0) in 5 patients, with a mean of 2.1 log copies/mL ± 1.2 log copies/mL plasma (median 1.9, range 1.0-4.6; Table 1). Treatment also induced an increase of the CD4 T-lymphocyte counts in 8 of 13 patients (average CD4 cell count after therapy: 840/µL ± 360/µL, median 790, range 353-1496). Surprisingly, the mean number of CD123+ DCs remained as low as before treatment (4450/mL ± 3970/mL blood, median 3100, P = .0009 compared with healthy donors; P = .59, ie, nonsignificant compared with before treatment; Table 2, Figure 3). Eight patients had decreased numbers, and 5 patients had higher numbers than before treatment initiation. Among these, 2 (no. 9 and no. 11) recovered numbers of CD123+ DCs close to the average number observed in noninfected controls. Patient no. 9 had the highest plasma viral load of the group before treatment (7.1 log copies/mL) and a relatively low CD4 lymphocyte count (371/µL), but after HAART, the patient's viral load became undetectable and his CD4 cell count normal (1428/µL). Moreover, this patient had a strikingly atypical clinical story: after HAART interruption at month 12, his viral load remained undetectable 6 months later. The viral load of patient no. 11 remained detectable, but his CD4 cell count was the highest of all patients after treatment (1496/µL). A strong correlation was found between CD123+ DC increase and CD4 T-cell count increase (P = .0009) (Figure 4A) and plasma viral load decrease (P = .009) (Figure 4B) after treatment.
The mean number of CD11c+ DCs was not restored by treatment either (5560/mL ± 4550/mL blood, median 3230; Table 2, Figure 3). It was lower than in healthy donors (P = .003), and not significantly different from before treatment (P = .64). The CD11c+ DC subpopulation became difficult to distinguish from other mononuclear, lineage-negative HLA-DRlow, CD11c+ populations in all but one patient. Five of 13 patients had higher CD11c+ DC numbers under treatment than before, but no correlation was found between this increase and viral loads or CD4 cell counts (Figure 4C, D; Table 2: compare patient no. 8 and patient no. 9 with patient no. 10). Therefore, HAART did not restore the average numbers of the 2 DC subpopulations, but some patients had higher numbers than before treatment initiation. Whereas CD11c+ DC number recovery did not correlate with viral load or CD4 cell count changes, CD123+ DC number recovery was strongly correlated with good virologic and immunologic parameters, and in one patient, restoration of normal CD123+ DC numbers was found together with a remarkable control of infection. Type I interferon plasma levels To help interpret the functional consequences of the decreased blood CD123+ DC numbers, type I IFN plasma levels were measured. All were undetectable (< 2 international units (IU)/mL), except for patient no. 12 at initiation of the study (8 IU/mL). These numbers are normal compared with healthy blood donors (< 2 IU/mL), and low compared with levels of more than 100 IU/mL found in birth-infected newborns from HIV-seropositive mothers (A. Krivine MD, St Vincent de Paul Hospital, P. Lebon, personal written communication, 1992) and 200 to 400 IU/mL in the first 10 days of experimental simian immunodeficiency virus (SIV) infection in macaques.37
The data presented here show for the first time a profound reduction of blood CD123+ DC numbers in primary HIV infection, and show at this stage of infection the blood CD11c+ DC number decrease that we had previously found in chronically HIV-infected patients.34 These are the first DC population alterations described in an infectious disease. These defects were found here as early as 26 to 57 days after the estimated date of infection, indicating that they were probably related to HIV itself rather than to the chronic activation of the immune system found in later stages of infection. Most interestingly, they were restored by antiretroviral treatment in only a few patients, and a strong correlation was found between CD123+ DC number recovery and good virologic and immunologic parameters. The striking clinical history of one of the patients, whose viral load remained undetectable as long as 6 months after HAART interruption, as already seen in other exceptional cases,17 coincides with a remarkable restoration of CD123+ (and CD11c+) DCs to normal numbers. Therefore, CD123+ DC number recovery under HAART could represent a predictor of viral control. In addition, the implications of this quantitative APC defect might be clues to design new strategies to enhance viral control. Potential causes of blood DC number reduction may be either
central or peripheral. In the periphery, DCs may have homed to lymphoid
organs and may no longer be in the blood. Comparative data from blood
and lymphoid organs are not available during primary infection. An
elevated frequency of CD1a+ DCs was found in
HIV+ patient tonsils38; these cells may
originate either from mucosal Langerhans cells or from blood DC
precursors.39 Alternately and not exclusively, DCs may be
destroyed in the periphery, either by the virus itself, by
CD8+ cytotoxic T lymphocytes, by a lack of
survival factors, or by other mechanisms. Conversely, the causes of DC
reduction may be central, with a decreased production of DCs from bone
marrow CD34+ or blood monocyte precursors, the latter being
suggested by the aspect of the flow cytometry data (Figure 2). In
vitro differentiation of CD11c+ DCs from HIV+
patient monocytes seems normal,40,41 but indirect
interactions may occur in the relevant microenvironment in vivo,
and in vitro infection data using different DCs and precursors are
needed. CD11c+ DCs with a lower HLA-DR
expression The potential consequences of the decreased numbers of DC populations in HIV infection are related to some of their functions: cytokine production (type I IFN, IL-12) and antigen presentation to naive T lymphocytes. CD123+ DCs are the natural interferon-producing cells.25,26 During chronic HIV infection, a defective type I IFN in vitro response of DCs to viral stimuli was shown.29 During experimental primary SIV infection in macaques, the peak of IFN-alpha secretion preceded that of antigenemia and levels became undetectable between 25 and 50 days after infection.37 In the patients studied here, all but one had undetectable levels at initiation of the study as well as 6 or 12 months later. The patient with a low but detectable level of plasma IFN was one of the earliest patients in the study (28 days, plasma drawn at the end of symptoms and 4 days after indeterminate WB) and had the second highest viral load (6.3 logs). The kinetics of type I IFN secretion still need to be studied in HIV+ patients, but if they parallel macaque studies, the peak may occur earlier than in the present study. Then reduction of CD123+ DC numbers might decrease this innate immune response, which was shown to be able to decrease HIV replication (reviewed in Khatissian et al37), to promote CD123+ DC survival, to increase TH1-type responses,24 and, together with GM-CSF, to mediate in vitro differentiation of DCs with strong HIV antigen presentation capacities in the severe combined immunodeficiency (SCID) mouse model.42 CD11c+ and CD123+ DCs secrete IL-12.23,24 Their reduced numbers may participate in the defective IL-12 responsiveness to inflammatory and viral stimuli that was found in PBMCs from HIV+ patients.43-46 This might contribute to the low IL-2 secretion by CD4+ T cells, because IL-12 was shown to restore in vitro IL-2 production from chronic HIV+ patient cells in response to HIV antigens.43,47 A consequence of low DC numbers may be a decreased ability to stimulate naive HIV-specific T lymphocytes. Indeed, Langerhans cells from HIV+ patients were deficient for allostimulation, hence naive T-cell stimulation, but not memory CD8+ T-cell activation.32,40 This would add to the T helper cell defect to explain the low T-cell responses during HIV primary infection. In addition, if DCs are not restored under HAART, naive T cells may not respond to viral antigens when HAART is interrupted. This may also hamper responses to therapeutic vaccination protocols currently undertaken under HAART to restore strong memory T-cell responses to the virus. It might be necessary to restore DC numbers before vaccination. This might be achieved, like CD4+ T-cell restoration, by long-term viral suppression,14,15 and might be improved by immune therapy. In combination with vaccination protocols under HAART, it may be necessary either to supplement DCs by IFN-alpha42 or IL-12 treatment if toxicity potential was overcome.44,47 Alternatively, it may be necessary to try and restore DC numbers using interleukins or molecules triggering DC survival, differentiation, and activation, like FLT3 ligand, GM-CSF, CD40 ligand trimers, IFN-gamma,43,46,48,49 alone or in combination. This might restart the positive feedback loop between DCs and T cells, and hopefully help stimulate stronger HIV-specific CD4+ and CD8+ T lymphocytes able to control HIV infection after HAART interruption. A larger proportion of infected individuals would then join the exceptional exposed, noninfected individuals or the long-term nonprogressors in a successful immune control of HIV replication.
We thank all the participating patients from the PRIMO cohort and their clinicians. We thank Sophie Maillet, Jean-Christophe Deschemin, Marion Dupuis, Alejandra Urrutia, and Joël Vega for skillful technical help; Muriel Andrieu and Cecile Cau for teaching FACS use; Sylvie Jacod-Le Borgne for help with statistical analysis; Michèle Villemur, the Etablissement de Transfusion Sanguine, and the donors for control blood; Claire Chougnet and Muriel Moser for helpful discussion and for carefully reading the manuscript; and Jean-Gérard Guillet and Jean-François Delfraissy for support.
Submitted June 14, 2001; accepted July 16, 2001.
Supported by the Agence Nationale de Recherche sur le SIDA (ANRS), Ensemble Contre le SIDA (Sidaction), and the Fondation pour la Recherche Médicale (J.P.).
J.P. and S.K. contributed equally to this work.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Anne Hosmalin, INSERM Unité 445, Institut Cochin de Génétique Moléculaire, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; e-mail: hosmalin{at}cochin.inserm.fr.
1.
Altfeld M, Rosenberg ES, Shankarappa R, et al.
Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.
J Exp Med.
2001;193:169-180 2. Lane HC, Depper JM, Greene WC, Whalen G, Waldmann TA, Fauci AS. Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome: evidence for a selective defect in soluble antigen recognition. N Engl J Med. 1985;313:79-84[Abstract]. 3. Clerici M, Stocks NI, Zajac RA, et al. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients: independence of CD4 cell numbers and clinical staging. J Clin Invest. 1989;84:1892-1899. 4. Dalod M, Dupuis M, Deschemin JC, et al. Weak anti-HIV CD8+ T cell effector activity in HIV primary infection. J Clin Invest. 1999;104:1431-1439[Medline] [Order article via Infotrieve]. 5. Champagne P, Ogg GS, King AS, et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature. 2001;410:106-111[CrossRef][Medline] [Order article via Infotrieve].
6.
Appay V, Nixon DF, Donahoe SM, et al.
HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function.
J Exp Med.
2000;192:63-75 7. Altfeld M, Rosenberg E. The role of CD4(+) T helper cells in the cytotoxic T lymphocyte response to HIV-1. Curr Opin Immunol. 2000;12:375-380[CrossRef][Medline] [Order article via Infotrieve]. 8. Heeney JL, Beverley P, McMichael A, et al. Immune correlates of protection from HIV and AIDS - more answers but yet more questions. Immunol Today. 1999;20:247-251[CrossRef][Medline] [Order article via Infotrieve].
9.
Letvin NL.
Progress in the development of an HIV-1 vaccine.
Science.
1998;280:1875-1880
10.
Carpenter CC, Cooper DA, Fischl MA, et al.
Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel.
JAMA.
2000;283:381-390
11.
Autran B, Carcelain G, Li TS, et al.
Positive effects of combined antiretroviral therapy on CD4+ cell homeostasis and function in advanced HIV disease.
Science.
1997;277:112-116
12.
Rosenberg ES, Billingsley JM, Caliendo AM, et al.
Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.
Science.
1997;278:1447-1450 13. Malhotra U, Berrey MM, Huang Y, et al. Effect of combination antiretroviral therapy on T-cell immunity in acute human immunodeficiency virus type 1 infection. J Inf Dis. 2000;181:121-131[CrossRef][Medline] [Order article via Infotrieve]. 14. Blankson JN, Gallant JE, Siliciano RF. Proliferative responses to HIV-1 antigens in HIV-1 infected patients with immune reconstitution. J Inf Dis. 2001;183:657-661[CrossRef][Medline] [Order article via Infotrieve]. 15. Angel JB, Parato KG, Kumar A, et al. Progressive HIV-specific immune recovery with prolonged viral suppression. J Inf Dis. 2001;183:546-554[CrossRef][Medline] [Order article via Infotrieve].
16.
Carcelain G, Tubiana R, Samri A, et al.
Transient mobilization of human immunodeficiency virus (HIV)-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection.
J Virol.
2001;75:234-241
17.
Lisziewicz J, Rosenberg E, Lieberman J, et al.
Control of HIV despite the discontinuation of antiretroviral therapy.
N Engl J Med.
1999;340:1683-1684 18. Mellors JW, Rinaldo CR Jr, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science. 1996;272:1167-1170[Abstract].
19.
Ogg G, Jin X, Bonhoeffer S, et al.
Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA.
Science.
1998;279:2103-2106 20. Goh WC, Markee J, Akridge RE, et al. Protection against human immunodeficiency virus type 1 infection in persons with repeated exposure: evidence for T cell immunity in the absence of inherited CCR5 coreceptor defects. J Inf Dis. 1999;179:548-557[CrossRef][Medline] [Order article via Infotrieve]. 21. Rowland-Jones SL, McMichael A. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Biol. 1995;7:448-455. 22. Banchereau J, Brière F, Caux C, et al. Immunobiology of dendritic cells. Ann Rev Immunol. 2000;18:767-811[CrossRef][Medline] [Order article via Infotrieve].
23.
Rissoan MC, Soumelis V, Kadowaki N, et al.
Reciprocal control of T helper cell and dendritic cell differentiation.
Science.
1999;283:1183-1186 24. Cella M, Facchetti F, Lanzavecchia A, Colonna M. Plasmacytoid dendritic cells activated by influenza virus and CD40L drive a potent TH1 polarization. Nature Immunology. 2000;1:305-310[CrossRef][Medline] [Order article via Infotrieve].
25.
Siegal F, Kadowaki N, Shodell M, et al.
The nature of the principal type 1 interferon-producing cells in human blood.
Science.
1999;284:1835-1837
26.
Kadowaki N, Antonenko S, Lau J, Liu Y.
Natural interferon a/b-producing cells link innate and adaptive immunity.
J Exp Med.
2000;192:219-225 27. McIlroy D, Autran B, Cheynier R, et al. Dendritic cell and CD4+ T lymphocyte infection frequency in spleens of HIV-positive patients. J Virol. 1995;69:4737-4745[Abstract]. 28. Steinman R. DC-SIGN: a guide to some mysteries of dendritic cells. Cell. 2000;100:491-494[CrossRef][Medline] [Order article via Infotrieve]. 29. Ferbas J, Navratil J, Logar A, Rinaldo C. Selective decrease in HIV-1-induced alpha interferon production by peripheral blood mononuclear cells during HIV-1 infection. Clin Diag Lab Immunol. 1995;2:138-142[Abstract]. 30. Fernandez N, Lozier A, Flament C, et al. Dendritic cells directly trigger NK cell functions: cross-talk relevant in innate anti-tumor responses in vivo. Nat Med. 1999;5:405-411[CrossRef][Medline] [Order article via Infotrieve]. 31. Knight SC, Macatonia SE. Effect of HIV on antigen presentation by dendritic cells and macrophages. Res Virol. 1991;142:123-128[CrossRef][Medline] [Order article via Infotrieve]. 32. Blauvelt A, Chougnet C, Shearer GM, Katz SI. Modulation of T cell responses to recall antigens presented by Langerhans cells in HIV-discordant identical twins by anti-IL-10 antibodies and IL-12. J Clin Invest. 1996;97:1550-1555[Medline] [Order article via Infotrieve]. 33. McIlroy D, Autran B, Clauvel J-P, Oksenhendler E, Debré P, Hosmalin A. Low CD83, but normal MHC class II and costimulatory molecule expression, on spleen dendritic cells from HIV+ patients. AIDS Res Hum Retr. 1998;14:505-513[Medline] [Order article via Infotrieve]. 34. Grassi FR, Hosmalin A, McIlroy D, Calvez V, Debré P, Autran B. CD11c-positive dendritic cells are depleted in the blood of HIV-infected patients. AIDS. 1999;13:759-766[CrossRef][Medline] [Order article via Infotrieve].
35.
Olweus J, BitMansour A, Warnke R, et al.
Dendritic cell ontogeny: a human dendritic cell lineage of myeloid ontogeny.
Proc Natl Acad Sci U S A.
1997;94:12551-12556 36. Gresser I, Bandu MT, Brouty-Boyé D, Tovey MG. Pronounced antiviral activity of human interferon on bovine and porcine cells. Nature. 1974;251:543-545[CrossRef][Medline] [Order article via Infotrieve]. 37. Khatissian E, Tovey MC, Cumont MC, et al. The relationship between the interferon alpha response and viral burden in primary SIV infection. AIDS Res Hum Retr. 1996;12:1273-1278[Medline] [Order article via Infotrieve]. 38. Behbahani H, Landay A, Patterson BK, et al. Normalization of immune activation in lymphoid tissue following highly active antiretroviral therapy. J Acquired Immune Defic Syndr. 2000;25:150-156.
39.
Ito T, Inaba M, Inaba K, et al.
A CD1a+/CD11c+ subset of human blood dendritic cells is a direct precursor of Langerhans cells.
J Immunol.
1999;163:1409-1419 40. Fan Z, Huang XL, Zheng L, et al. Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection. J Immunol. 1997;159:4973-4982[Abstract].
41.
Chougnet C, Cohen SS, Kawamura T, et al.
Normal immune function of monocyte-derived dendritic cells from HIV-infected individuals: implications for immunotherapy.
J Immunol.
1999;163:1666-1673
42.
Santini SM, Lapenta C, Logozzi M, et al.
Type I interferon as a powerful adjuvant for monocyte-derived dendritic cell development and activity in vitro and in Hu-PBL-SCID mice.
J Exp Med.
2000;191:1777-1788 43. Chougnet C, Thomas E, Landay AL, et al. CD40 ligand and IFN-gamma synergistically restore IL-12 production in HIV-infected patients. Eur J Immunol. 1998;28:646-656[CrossRef][Medline] [Order article via Infotrieve]. 44. Chougnet C, Wynn TA, Clerici M, et al. Molecular analysis of decreased interleukin-12 production in persons infected with human immunodeficiency virus. J Inf Dis. 1996;174:46-53[Medline] [Order article via Infotrieve].
45.
Marshall J, Chehimi J, Gri G, Kostman J, Montaner L, Trinchieri G.
The IL-12-mediated pathway of immune events is dysfunctional in HIV-infected individuals.
Blood.
1999;94:1003-1011 46. Vanham G, Penne L, Devalck J, et al. Decreased CD40 ligand induction in CD4 T cells and dysregulated IL-12 production during HIV infection. Clin Exp Immunol. 1999;117:335-342[CrossRef][Medline] [Order article via Infotrieve]. 47. Jacobson MA, Hardy D, Connick E, Watson J, DeBruin M. Phase 1 trial of a single dose of recombinant human interleukin-12 in human immunodeficiency virus-infected patients with 100-500 CD4 cells/microL. J Inf Dis. 2000;182:1070-1076[CrossRef][Medline] [Order article via Infotrieve].
48.
Ostrowski M, Justement S, Ehler L, et al.
The role of CD4+ T cell help and CD40 ligand in the in vitro expansion of HIV-1 specific memory CD8+ T cell responses.
J Immunol.
2000;165:6133-6141 49. Diehl L, Boer ATd, Schoenberger SP, et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med. 1999;5:774-779[CrossRef][Medline] [Order article via Infotrieve].
© 2001 by The American Society of Hematology.
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  S Mori and P Levin A brief review of potential mechanisms of immune reconstitution inflammatory syndrome in HIV following antiretroviral therapy Int J STD AIDS, July 1, 2009; 20(7): 447 - 452. [Abstract] [Full Text] [PDF]
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|
 E. L. Turnbull, M. Wong, S. Wang, X. Wei, N. A. Jones, K. E. Conrod, D. Aldam, J. Turner, P. Pellegrino, B. F. Keele, et al. Kinetics of Expansion of Epitope-Specific T Cell Responses during Primary HIV-1 Infection J. Immunol., June 1, 2009; 182(11): 7131 - 7145. [Abstract] [Full Text] [PDF]
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|
|
 |
|
 C. Lecuroux, I. Girault, A. Urrutia, J.-M. Doisne, C. Deveau, C. Goujard, L. Meyer, M. Sinet, and A. Venet Identification of a particular HIV-specific CD8+ T-cell subset with a CD27+ CD45RO-/RA+ phenotype and memory characteristics after initiation of HAART during acute primary HIV infection Blood, April 2, 2009; 113(14): 3209 - 3217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Liu, A. M. Woltman, H. L. A. Janssen, and A. Boonstra Modulation of dendritic cell function by persistent viruses J. Leukoc. Biol., February 1, 2009; 85(2): 205 - 214. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Malleret, B. Maneglier, I. Karlsson, P. Lebon, M. Nascimbeni, L. Perie, P. Brochard, B. Delache, J. Calvo, T. Andrieu, et al. Primary infection with simian immunodeficiency virus: plasmacytoid dendritic cell homing to lymph nodes, type I interferon, and immune suppression Blood, December 1, 2008; 112(12): 4598 - 4608. [Abstract] [Full Text] [PDF]
|
|
|
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 |
|
 S. Haupt, N. Donhauser, C. Chaipan, P. Schuster, B. Puffer, R. S. Daniels, T. C. Greenough, F. Kirchhoff, and B. Schmidt CD4 Binding Affinity Determines Human Immunodeficiency Virus Type 1-Induced Alpha Interferon Production in Plasmacytoid Dendritic Cells J. Virol., September 1, 2008; 82(17): 8900 - 8905. [Abstract] [Full Text] [PDF]
|
|
|
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|
S. McCormick, M. Santosuosso, C.-L. Small, C. R. Shaler, X. Zhang, M. Jeyanathan, J. Mu, S. Takenaka, P. Ngai, J. Gauldie, et al. Mucosally Delivered Dendritic Cells Activate T Cells Independently of IL-12 and Endogenous APCs J. Immunol., August 15, 2008; 181(4): 2356 - 2367. [Abstract] [Full Text] [PDF]
|
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N. Sachdeva, V. Asthana, T. H. Brewer, D. Garcia, and D. Asthana Impaired Restoration of Plasmacytoid Dendritic Cells in HIV-1-Infected Patients with Poor CD4 T Cell Reconstitution Is Associated with Decrease in Capacity to Produce IFN-{alpha} but Not Proinflammatory Cytokines J. Immunol., August 15, 2008; 181(4): 2887 - 2897. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. M. Diop, M. J.-Y. Ploquin, L. Mortara, A. Faye, B. Jacquelin, D. Kunkel, P. Lebon, C. Butor, A. Hosmalin, F. Barre-Sinoussi, et al. Plasmacytoid Dendritic Cell Dynamics and Alpha Interferon Production during Simian Immunodeficiency Virus Infection with a Nonpathogenic Outcome J. Virol., June 1, 2008; 82(11): 5145 - 5152. [Abstract] [Full Text] [PDF]
|
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|
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K. N. Brown, A. Trichel, and S. M. Barratt-Boyes Parallel Loss of Myeloid and Plasmacytoid Dendritic Cells from Blood and Lymphoid Tissue in Simian AIDS J. Immunol., June 1, 2007; 178(11): 6958 - 6967. [Abstract] [Full Text] [PDF]
|
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A. Biancotto, J.-C. Grivel, S. J. Iglehart, C. Vanpouille, A. Lisco, S. F. Sieg, R. Debernardo, K. Garate, B. Rodriguez, L. B. Margolis, et al. Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1 Blood, May 15, 2007; 109(10): 4272 - 4279. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Martinelli, C. Cicala, D. Van Ryk, D. J. Goode, K. Macleod, J. Arthos, and A. S. Fauci HIV-1 gp120 inhibits TLR9-mediated activation and IFN-{alpha} secretion in plasmacytoid dendritic cells PNAS, February 27, 2007; 104(9): 3396 - 3401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Teleshova, J. Kenney, G. Van Nest, J. Marshall, J. D. Lifson, I. Sivin, J. Dufour, R. Bohm, A. Gettie, and M. Robbiani Local and Systemic Effects of Intranodally Injected CpG-C Immunostimulatory-Oligodeoxyribonucleotides in Macaques J. Immunol., December 15, 2006; 177(12): 8531 - 8541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Chougnet and S. Gessani Role of gp120 in dendritic cell dysfunction in HIV infection J. Leukoc. Biol., November 1, 2006; 80(5): 994 - 1000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hosmalin and P. Lebon Type I interferon production in HIV-infected patients J. Leukoc. Biol., November 1, 2006; 80(5): 984 - 993. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Donaghy, J. Wilkinson, and A. L. Cunningham HIV interactions with dendritic cells: has our focus been too narrow? J. Leukoc. Biol., November 1, 2006; 80(5): 1001 - 1012. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Zaunders, S. Ip, M. L. Munier, D. E. Kaufmann, K. Suzuki, C. Brereton, S. C. Sasson, N. Seddiki, K. Koelsch, A. Landay, et al. Infection of CD127+ (Interleukin-7 Receptor+) CD4+ Cells and Overexpression of CTLA-4 Are Linked to Loss of Antigen-Specific CD4 T Cells during Primary Human Immunodeficiency Virus Type 1 Infection. J. Virol., October 1, 2006; 80(20): 10162 - 10172. [Abstract] [Full Text] [PDF]
|
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|
|
|
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F. Groot, T. M. M. van Capel, M. L. Kapsenberg, B. Berkhout, and E. C. de Jong Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition Blood, September 15, 2006; 108(6): 1957 - 1964. [Abstract] [Full Text] [PDF]
|
|
|
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Z. Zhang, J. Fu, Q. Zhao, Y. He, L. Jin, H. Zhang, J. Yao, L. Zhang, and F.-S. Wang Differential Restoration of Myeloid and Plasmacytoid Dendritic Cells in HIV-1-Infected Children after Treatment with Highly Active Antiretroviral Therapy J. Immunol., May 1, 2006; 176(9): 5644 - 5651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
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R. Zhang, J. D. Lifson, and C. Chougnet Failure of HIV-exposed CD4+ T cells to activate dendritic cells is reversed by restoration of CD40/CD154 interactions Blood, March 1, 2006; 107(5): 1989 - 1995. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
A. Granelli-Piperno, I. Shimeliovich, M. Pack, C. Trumpfheller, and R. M. Steinman HIV-1 Selectively Infects a Subset of Nonmaturing BDCA1-Positive Dendritic Cells in Human Blood J. Immunol., January 15, 2006; 176(2): 991 - 998. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
S. Patterson, H. Donaghy, P. Amjadi, B. Gazzard, F. Gotch, and P. Kelleher Human BDCA-1-Positive Blood Dendritic Cells Differentiate into Phenotypically Distinct Immature and Mature Populations in the Absence of Exogenous Maturational Stimuli: Differentiation Failure in HIV Infection J. Immunol., June 15, 2005; 174(12): 8200 - 8209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
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N. N. Meissner, S. Swain, M. Tighe, A. Harmsen, and A. Harmsen Role of Type I IFNs in Pulmonary Complications of Pneumocystis murina Infection J. Immunol., May 1, 2005; 174(9): 5462 - 5471. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Jiang, M. M. Lederman, J. R. Salkowitz, B. Rodriguez, C. V. Harding, and S. F. Sieg Impaired Monocyte Maturation in Response to CpG Oligodeoxynucleotide Is Related to Viral RNA Levels in Human Immunodeficiency Virus Disease and Is at Least Partially Mediated by Deficiencies in Alpha/Beta Interferon Responsiveness and Production J. Virol., April 1, 2005; 79(7): 4109 - 4119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Chung, S. B. Amrute, K. Abel, G. Gupta, Y. Wang, C. J. Miller, and P. Fitzgerald-Bocarsly Characterization of Virus-Responsive Plasmacytoid Dendritic Cells in the Rhesus Macaque Clin. Vaccine Immunol., March 1, 2005; 12(3): 426 - 435. [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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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]
|
|
|
|
|
|
K. B. Gurney, A. D. Colantonio, B. Blom, H. Spits, and C. H. Uittenbogaart Endogenous IFN-{alpha} Production by Plasmacytoid Dendritic Cells Exerts an Antiviral Effect on Thymic HIV-1 Infection J. Immunol., December 15, 2004; 173(12): 7269 - 7276. [Abstract] [Full Text] [PDF]
|
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|
 |
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 L. de Repentigny, D. Lewandowski, and P. Jolicoeur Immunopathogenesis of Oropharyngeal Candidiasis in Human Immunodeficiency Virus Infection Clin. Microbiol. Rev., October 1, 2004; 17(4): 729 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
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J.-M. Doisne, A. Urrutia, C. Lacabaratz-Porret, C. Goujard, L. Meyer, M.-L. Chaix, M. Sinet, and A. Venet CD8+ T Cells Specific for EBV, Cytomegalovirus, and Influenza Virus Are Activated during Primary HIV Infection J. Immunol., August 15, 2004; 173(4): 2410 - 2418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Teleshova, J. Kenney, J. Jones, J. Marshall, G. Van Nest, J. Dufour, R. Bohm, J. D. Lifson, A. Gettie, and M. Pope CpG-C Immunostimulatory Oligodeoxyribonucleotide Activation of Plasmacytoid Dendritic Cells in Rhesus Macaques to Augment the Activation of IFN-{gamma}-Secreting Simian Immunodeficiency Virus-Specific T Cells J. Immunol., August 1, 2004; 173(3): 1647 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Larsson, E. Babcock, A. Grakoui, N. Shoukry, G. Lauer, C. Rice, C. Walker, and N. Bhardwaj Lack of Phenotypic and Functional Impairment in Dendritic Cells from Chimpanzees Chronically Infected with Hepatitis C Virus J. Virol., June 15, 2004; 78(12): 6151 - 6161. [Abstract] [Full Text] [PDF]
|
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C. Carbonneil, V. Donkova-Petrini, A. Aouba, and L. Weiss Defective Dendritic Cell Function in HIV-Infected Patients Receiving Effective Highly Active Antiretroviral Therapy: Neutralization of IL-10 Production and Depletion of CD4+CD25+ T Cells Restore High Levels of HIV-Specific CD4+ T Cell Responses Induced by Dendritic Cells Generated in the Presence of IFN-{alpha} J. Immunol., June 15, 2004; 172(12): 7832 - 7840. [Abstract] [Full Text] [PDF]
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N. Teleshova, J. Jones, J. Kenney, J. Purcell, R. Bohm, A. Gettie, and M. Pope Short-term Flt3L treatment effectively mobilizes functional macaque dendritic cells J. Leukoc. Biol., June 1, 2004; 75(6): 1102 - 1110. [Abstract] [Full Text] [PDF]
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V. Reddy, J. A. Iturraspe, A. C. Tzolas, H.-U. Meier-Kriesche, J. Schold, and J. R. Wingard Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease Blood, June 1, 2004; 103(11): 4330 - 4335. [Abstract] [Full Text] [PDF]
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P. Bjorck Dendritic Cells Exposed to Herpes Simplex Virus In Vivo Do Not Produce IFN-{alpha} after Rechallenge with Virus In Vitro and Exhibit Decreased T Cell Alloreactivity J. Immunol., May 1, 2004; 172(9): 5396 - 5404. [Abstract] [Full Text] [PDF]
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J. Poudrier, X. Weng, D. G. Kay, Z. Hanna, and P. Jolicoeur The AIDS-Like Disease of CD4C/Human Immunodeficiency Virus Transgenic Mice Is Associated with Accumulation of Immature CD11bHi Dendritic Cells J. Virol., November 1, 2003; 77(21): 11733 - 11744. [Abstract] [Full Text] [PDF]
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S. Turville, J. Wilkinson, P. Cameron, J. Dable, and A. L. Cunningham The role of dendritic cell C-type lectin receptors in HIV pathogenesis J. Leukoc. Biol., November 1, 2003; 74(5): 710 - 718. [Abstract] [Full Text] [PDF]
|
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C. Chougnet Role of CD40 Ligand dysregulation in HIV-associated dysfunction of antigen-presenting cells J. Leukoc. Biol., November 1, 2003; 74(5): 702 - 709. [Abstract] [Full Text] [PDF]
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K. Lore, M. R. Betts, J. M. Brenchley, J. Kuruppu, S. Khojasteh, S. Perfetto, M. Roederer, R. A. Seder, and R. A. Koup Toll-Like Receptor Ligands Modulate Dendritic Cells to Augment Cytomegalovirus- and HIV-1-Specific T Cell Responses J. Immunol., October 15, 2003; 171(8): 4320 - 4328. [Abstract] [Full Text] [PDF]
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 G. M. Bahr, X. De La Tribonniere, E. Darcissac, F. Ajana, L. Bocket, D. Sissoko, Y. Yazdanpanah, J. Dewulf, C. Amiel, and Y. Mouton Clinical and immunological effects of a 6 week immunotherapy cycle with murabutide in HIV-1 patients with unsuccessful long-term antiretroviral treatment J. Antimicrob. Chemother., June 1, 2003; 51(6): 1377 - 1388. [Abstract] [Full Text] [PDF]
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H. Donaghy, B. Gazzard, F. Gotch, and S. Patterson Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1 Blood, June 1, 2003; 101(11): 4505 - 4511. [Abstract] [Full Text] [PDF]
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D. Verthelyi, M. Gursel, R. T. Kenney, J. D. Lifson, S. Liu, J. Mican, and D. M. Klinman CpG Oligodeoxynucleotides Protect Normal and SIV-Infected Macaques from Leishmania Infection J. Immunol., May 1, 2003; 170(9): 4717 - 4723. [Abstract] [Full Text] [PDF]
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Y. K. Choi, B. A. Fallert, M. A. Murphey-Corb, and T. A. Reinhart Simian immunodeficiency virus dramatically alters expression of homeostatic chemokines and dendritic cell markers during infection in vivo Blood, March 1, 2003; 101(5): 1684 - 1691. [Abstract] [Full Text] [PDF]
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K. Abel, M. J. Alegria-Hartman, K. Rothaeusler, M. Marthas, and C. J. Miller The Relationship between Simian Immunodeficiency Virus RNA Levels and the mRNA Levels of Alpha/Beta Interferons (IFN-{alpha}/{beta}) and IFN-{alpha}/{beta}-Inducible Mx in Lymphoid Tissues of Rhesus Macaques during Acute and Chronic Infection J. Virol., July 17, 2002; 76(16): 8433 - 8445. [Abstract] [Full Text] [PDF]
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J. Chehimi, D. E. Campbell, L. Azzoni, D. Bacheller, E. Papasavvas, G. Jerandi, K. Mounzer, J. Kostman, G. Trinchieri, and L. J. Montaner Persistent Decreases in Blood Plasmacytoid Dendritic Cell Number and Function Despite Effective Highly Active Antiretroviral Therapy and Increased Blood Myeloid Dendritic Cells in HIV-Infected Individuals J. Immunol., May 1, 2002; 168(9): 4796 - 4801. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
DCs of the multistratified epithelia
P9), anti-CD16
(3G8), anti-CD19 (SJ25C1), anti-CD20 (L27) and anti-CD56 (NCAM 16-2) (Becton Dickinson, Le Pont de Claix, France).
