Aberrant expression of CD27 and soluble CD27 (sCD27) in HIV infection and in AIDS-associated lymphoma.

CD27 is a member of the tumor necrosis factor receptor superfamily that is expressed primarily on T cells, as well as on subsets of B cells and NK cells. CD70, which is expressed on activated B and T cells, but not on resting lymphocytes, is a ligand for CD27. Cell surface CD27 can be proteolytically cleaved to produce a 32-kDa soluble CD27 (sCD27) molecule. Elevated levels of sCD27 are seen in a number of disease states and malignancies. Although it has been reported that cerebrospinal fluid sCD27 levels were elevated in people who had AIDS dementia, little is known about CD27 expression in HIV disease. To determine if sCD27 levels were elevated in those with HIV infection, and/or in those with AIDS-associated non-Hodgkin's lymphoma (AIDS-NHL), sCD27 levels were measured in HIV-negative and HIV-positive subjects as well as in people who developed AIDS-NHL. Serum sCD27 levels were seen to be elevated in HIV+ subjects. Furthermore, sCD27 levels were particularly elevated in those subjects who went on to develop AIDS-NHL, with serum sCD27 levels in AIDS-NHL subjects being significantly higher than those in HIV+ subjects who did not develop lymphoma. Most AIDS-NHL cell lines and primary AIDS-NHL tumor specimens expressed both CD27 and its ligand, CD70. The proportion of circulating B cells that expressed cell surface CD27 was substantially reduced in those with HIV infection, and B cells from HIV-infected subjects produced decreased levels of sCD27 in culture. Together, these results indicate that CD27/sCD27 expression is abnormal in HIV infection and suggest that this molecule merits further examination as a potential marker for AIDS-NHL.     

Non-Hodgkin's B cell lymphoma in persons with acquired immunodeficiency syndrome is associated with increased serum levels of IL10, or the IL10 promoter -592 C/C genotype

Interleukin-10 (IL10) may contribute to the development of non-Hodgkin's B cell lymphoma, especially in the context of acquired immunodeficiency syndrome (AIDS), where lymphoma incidence is greatly increased. Utilizing specimens from the Multicenter AIDS Cohort Study (MACS) obtained prior to diagnosis of AIDS-associated lymphoma, detectable serum human IL10 was seen much more frequently in lymphoma cases (n = 61, 26%) compared to CD4-matched AIDS controls (5%, P = 0.004), or to HIV-infected (2%, P = 0.002) or HIV uninfected subjects (0%, P = 0.0003). In longitudinal studies, detectable IL10 occurred at times closest to but preceding lymphoma diagnosis (P = 0.01). In an independent genetic analysis of single-nucleotide polymorphisms within the promoter region of the IL10 gene in 1157 MACS subjects, a high IL10-expressing genotype (-592 C/C) was overrepresented among lymphoma subjects (P = 0.009), even when controlling for race (P = 0.006). These results suggest that elevated serum IL10 or the IL10 promoter -592 C/C genotype are associated with development of AIDS lymphoma.     

Serum levels of the homeostatic B cell chemokine, CXCL13, are elevated during HIV infection.

HIV infection is associated with B cell dysfunction, which includes B cell hyperactivation, hypergammaglobulinemia, impaired production of antibodies against specific antigens, and a loss of B cell memory. Because lymph node architecture is progressively destroyed during HIV infection, it is possible that normal B cell trafficking is impaired as well, which could be a cause or a result of these abnormalities. Because the homeostatic chemokine, CXCL13 (BLC, BCA-1), is a major regulator of B cell trafficking, we assessed circulating levels of this molecule in HIV infection. Serum levels of CXCL13 were seen to be progressively elevated in HIV disease. Serum levels of CXCL13 correlated strongly with those of the inflammation-associated chemokine, inducible protein-10 (IP-10), in subjects who had advanced HIV disease, and more moderately with levels of soluble CD30 (sCD30), sCD27, and sCD23. CXCL13 levels also correlated moderately with viral load and showed a significant decline after use of highly active antiretroviral treatment (HAART). Elevated levels of CXCL13 could cause impaired or altered trafficking of B cells during HIV infection and could contribute to the previously reported loss of CXCR5, the receptor for CXCL13, from the surface of circulating B cells in HIV infection.     

Serum sCD23 Level in Patients with AIDS-Related Non-Hodgkin''s Lymphoma Is Associated with Absence of Epstein–Barr Virus in Tumor Tissue

The cytokine soluble CD23 (sCD23) acts as a B cell growth factor and is associated with Epstein–Barr virus (EBV) infection. To elucidate the role sCD23 might play in the pathogenesis of AIDS-related non-Hodgkin's lymphoma (AIDS NHL), 101 AIDS NHL patients from the Multicenter AIDS Cohort Study were studied. Serum sCD23 within 18 months prior to lymphoma diagnosis was measured for all patients and EBV in tumor tissue was ascertained for 49 patients. Tumor morphology and primary site were verified from pathology reports and tumor specimens. Bivariate tests and multivariate regression were employed to determine whether serum sCD23 correlated with tumor EBV, morphology, and primary site. Higher levels of serum sCD23 were associated with the absence of tumor EBV and with small noncleaved cell morphology. Thus, the serum sCD23 level does not appear to be mediated by EBV in these patients, but could be related to a pathogenetic mechanism of small noncleaved cell lymphoma.     

Serum sCD23 level in patients with AIDS-related non-Hodgkin's lymphoma is associated with absence of Epstein-Barr virus in tumor tissue

The cytokine soluble CD23 (sCD23) acts as a B cell growth factor and is associated with Epstein-Barr virus (EBV) infection. To elucidate the role sCD23 might play in the pathogenesis of AIDS-related non-Hodgkin's lymphoma (AIDS NHL), 101 AIDS NHL patients from the Multicenter AIDS Cohort Study were studied. Serum sCD23 within 18 months prior to lymphoma diagnosis was measured for all patients and EBV in tumor tissue was ascertained for 49 patients. Tumor morphology and primary site were verified from pathology reports and tumor specimens. Bivariate tests and multivariate regression were employed to determine whether serum sCD23 correlated with tumor EBV, morphology, and primary site. Higher levels of serum sCD23 were associated with the absence of tumor EBV and with small noncleaved cell morphology. Thus, the serum sCD23 level does not appear to be mediated by EBV in these patients, but could be related to a pathogenetic mechanism of small noncleaved cell lymphoma.     

Serum soluble CD23 in patients with hypogammaglobulinaemia.

Serum levels of the soluble form of the low-affinity receptor for IgE (FcERII, CD23) (sCD23) are elevated in autoimmune conditions associated with hypergammaglobulinaemia and B cell hyperactivity. Very high levels of sCD23 are found in patients with B-chronic lymphatic leukaemia (B-CLL) who are, however, frequently hypogammaglobulinaemic. We therefore compared the serum levels of sCD23 in healthy controls (n = 33) with three conditions associated with hypogammaglobulinaemia (HGG) and varying B cell numbers: X-linked agammaglobulinaemia (XLA, n = 12), common variable immunodeficiency (CVI, n = 20) and B-chronic lymphatic leukaemia (n = 33). Serum levels of sCD23 showed a significant correlation with the CD19+ B cell count in both normals and patients with CVI (r = 0.65, P < 0.0001). Amongst the different clinical groups, serum levels of sCD23 were increased in the order XLA < CVI < normals < CLL (medians 2.5, 7.7, 11.1 and 540, respectively; P < 0.001 for all comparisons except CVI versus normals P < 0.03 in a one-tailed test). In the CVI group, serum sCD23 was lowest amongst four patients with low B cell numbers. There was no overlap in sCD23 between patients with XLA and this subgroup of CVI patients. Serum sCD23 is, therefore, derived predominantly from B cells, and is significantly related to the peripheral blood B cell count.     

Increased soluble CD14 serum levels and altered CD14 expression of peripheral blood monocytes in HIV-infected patients.

Serum levels of soluble CD14 were elevated in HIV-infected asymptomatic patients or those with lymphadenopathy (CDC II/III) 2.9 +/- 0.8 mg/l compared with normal controls with 2.2 +/- 0.47 mg/l, P < 0.001. A further rise was seen in patients with ARC (CDC IVA) 3.8 +/- 1.1 mg/l, P < 0.01 and patients with AIDS (CDC IVB-D) 5.7 +/- 2.5 mg/l, P < 0.01. Although absolute numbers of CD14+ cells decrease in the AIDS group, the percentage of CD14+ monocytes did not change. In contrast, levels of soluble T cell antigens sCD4 and sCD8, which are higher in HIV-infected patients compared with normal subjects, showed no increase with disease progression. Serum levels of sCD14 were correlated positively with beta 2-microglobulin levels (rs = 0.63, P < 0.0001). Whereas the percentage of CD14+ monocytes did not change, an increase in monocytic CD14 expression in HIV-infected patients was observed (P < 0.01). The percentage of a monocyte subset expressing both CD14 and CD16 increased from 6% in normal healthy persons to 13% in HIV-infected patients (P < 0.001), and did not vary between the HIV patient groups. Incubation of cultured peripheral blood monocytes with azidothymidine had no effect on either normal or LPS-induced or IL-4-inhibited sCD14 release in vitro. Therefore, an effect of AZT on sCD14 serum values in vivo is considered to be unlikely. Our data further provide evidence that monocytes/macrophages are engaged in HIV infection.     

Serum measurements of soluble CD23 in HIV infection.

A gradual reduction in cell-mediated immunity is thought to occur with the progression of human immunodeficiency virus (HIV) infection. This suggests a selective attrition of the Th1 subset. The regulation of the soluble form of the low-affinity receptor for IgE (sCD23) by the opposing actions of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) allows the assessment of the overall balance of Th1 to Th2 activity in a given disease. In order to investigate this further we employed an enhanced chemiluminescent ELISA to analyse serum levels of sCD23 in male subjects with and without HIV infection. Serum levels of sCD23 were similar in 34 HIV seronegative homosexuals, 39 homosexuals with asymptomatic HIV infection, 27 homosexuals with acquired immune deficiency syndrome (AIDS) and 20 healthy controls. This suggests that HIV has no predilection for either the Th1 or Th2 subsets of CD4 T cells.     

Ex vivo modulation of RANTES and sCD30 by proinflammatory stimuli in HIV-seropositive and -negative individuals

RANTES and sCD30 were measured in ex vivo culture supernatants of unstimulated or stimulated PBMC in order to investigate their potential role as markers of acute immune activation. Patients in an advanced stage of HIV infection (AIDS A) were compared to AIDS patients who were evaluated for pneumonia at the time of blood withdrawal (AIDS B); HIV(+) individuals with nonprogressive infection (LTNP) and healthy donors (N) served as controls. Constitutive levels of RANTES were significantly elevated in AIDS B patients (P 0.0001), whereas spontaneous release of sCD30 was strongly correlated with the presence of both pneumonia (P 0.002) and HIV infection (P 0.004). LPS was a strong inducer of RANTES in all four categories; however, in AIDS B patients a negative and positive correlation between constitutive and induced levels was observed with LPS (P 0.0004) and IFN-gamma (P 0.006), respectively. We clearly showed that IFN-gamma reached a fourfold superinduction of sCD30 release in both HIV-positive and -negative individuals, whereas IL-6-driven production of both sCD30 and RANTES occurred only in healthy donors. Ex vivo RANTES levels may also be monitored as an index of acute immune activation under conditions of chronic activation of the immune system, whereas sCD30 release may be equally indicative of both acute and chronic processes of T cell activation. Proinflammatory stimuli differentially affected RANTES and sCD30 secretion in ex vivo PBMC cultures, suggesting complex pathways in the in vivo regulation of these two molecules.     

Human recombinant interleukin 4 induces normal B cells to produce soluble CD23/IgE-binding factor analogous to that spontaneously released by lymphoblastoid B cell lines

Surface-labeled Epstein-Barr virus (EBV)-transformed lymphoblastoid RPMI 8866 cells release in their supernatant a radiolabeled 25-kDa polypeptide which reacts with the Fc epsilon RL/CD23-specific monoclonal antibody (mAb) 25 and which binds to IgE but not IgG (IgE BF/sCD23). IgE BF/sCD23 had an isoelectric point of 4.5-5.0. The reactivity of mAb 25 with IgE BF/sCD23 allowed us to set up a radioimmunoassay for detection of IgE BF/sCD23 in cell culture supernatants. Supernatants from Fc epsilon RL/CD23+ cell lines were found to contain IgE BF/sCD23. Addition of human recombinant interleukin 4 (IL 4) to normal human B cells cultures induced the production of IgE BF/sCD23. Activation of B cells with anti-IgM antibody coupled to beads enhanced the IL 4-induced production of IgE BF/sCD23 when compared to nonactivated B cells. This correlates with the finding that anti-IgM antibody-activated B cells cultured with IL 4 express more Fc epsilon RL/CD23 than B cells cultured with IL 4 alone. The biochemical characteristics of radiolabeled IgE BF/sCD23 immunoprecipitated by mAb 25 from the supernatants of normal B cells cultured with IL 4 were identical to those of the IgE BF/sCD23 isolated from EBV-transformed cell line supernatants. Addition of interferon-gamma to B cells cultured with IL 4 strongly decreased the level of IgE BF/sCD23 in culture supernatants correlating with the observed decrease of Fc epsilon RL/CD23 on B cell surface. These data demonstrate that normal human B cells cultured in the presence of IL 4 produce an IgE-binding factor (sCD23) biochemically and antigenically equivalent to that spontaneously produced by EBV-transformed lymphoblastoid cell lines.     

An evaluation of serum soluble CD30 levels and serum CD26 (DPPIV) enzyme activity as markers of type 2 and type 1 cytokines in HIV patients receiving highly active antiretroviral therapy.

This study evaluates serum CD26 (dipeptidyl peptidase IV, DPPIV) enzyme activity and serum levels of soluble CD30 as markers of T1 and T2 cytokine environments in HIV patients who achieved immune reconstitution after highly active antiretroviral therapy (HAART). Patients who had experienced inflammatory disease associated with pre-existent opportunistic infections after HAART (immune restoration diseases, IRD) were considered separately. Serum sCD30 levels and CD26 (DPPIV) enzyme activity were compared with IFN-gamma production by PBMC cultured with cytomegalovirus (CMV) antigen in controls and patient groups. High sCD30 levels were associated with low IFN-gamma production after antigenic stimulation in control subjects and, to a lesser extent, in immune reconstituted HIV patients. There was no association between serum CD26 (DPPIV) enzyme activity and IFN-gamma production or sCD30 levels. Serum sCD30 levels and CD26 (DPPIV) enzyme activity were significantly increased in immune reconstituted patients with high HIV viral loads. Patients who had experienced CMV retinitis as an IRD had significantly higher sCD30 levels than all other patient groups. Hence, high sCD30 levels may be a marker of a T2 cytokine environment in HIV patients with immune reconstitution and are associated with higher HIV viral loads and a history of CMV associated IRD.     

Circulating elevated levels of soluble CD23, interleukin-4, and CD20+CD23+ lymphocytes in atopic subjects with elevated serum IgE concentrations.

Circulating IgE protein levels, leukocyte counts, lymphocyte subsets, IL-4, and soluble CD23 levels were quantitated in 43 atopic and 19 nonatopic subjects. Mean values of IgE protein levels, total eosinophil counts, CD20+CD23+ cells (B cells with low-affinity IgE receptor), IL-4 and sCD23 levels were elevated in atopic patients compared with nonatopic controls. The results suggest that sCD23, IL-4, and CD20+CD23+ lymphocytes may play a role in the increased production of IgE in atopic subjects in a manner similar to that observed by other investigators in prior in vitro studies.     

Soluble CD23 levels are elevated in the serum of patients with primary Sjögren''s syndrome and systemic lupus erythematosus.

The low affinity IgE receptor Fc epsilon RII (CD23) is important in several aspects of T and B cell function. In this study serum levels of soluble CD23 (sCD23) were measured in three groups: 26 female patients with systemic lupus erythematosus (SLE), 21 females with primary Sjögren''s syndrome (pSS) and 25 normal healthy females. The concentration of sCD23 was determined using an enhanced chemiluminescent sandwich ELISA developed in this laboratory. Increased levels of sCD23 were observed in pSS and in SLE patients compared with controls (median 23.0 versus 8.6, P less than 0.0002 and 18.1 versus 8.6, P less than 0.002 respectively). While the median level of sCD23 was found to be higher in pSS than in SLE the difference was not statistically significant. Patients with SLE and pSS on glucocorticoid treatment had significantly lower levels of sCD23 than patients not on this treatment (median 28.9 versus 14.4, P less than 0.05). Amongst the control patients sCD23 was inexplicably lower in the female members relative to the males (median 8.5 versus 12.3, P less than 0.05). Although serum IgG and IgA levels were significantly elevated in pSS and SLE patients relative to controls there was no direct correlation between sCD23 and the serum levels of these immunoglobulins. We conclude that B cell hyperactivity which occurs in both pSS and SLE is associated with raised levels of sCD23.     

Triggering through CD40 promotes interleukin-4-induced CD23 production and enhanced soluble CD23 release in atopic disease

The pathogenesis of atopic disease is closely linked to the overproduction of IgE. CD23 and CD40 are two cellular receptors involved in the regulation of IgE production and both receptors are elevated in atopic disease. We have examined the role of CD40 in the regulation of CD23 and soluble CD23 production in healthy and atopic donors. Triggering of the B cell CD40 receptor directly enhances interleukin (IL)-4-mediated up-regulation of CD23 at both the protein and the mRNA level. When atopic donors were studied, the synergistic effect of CD40 triggering on the IL-4-induced up-regulation of CD23 and soluble CD23 (sCD23) was enhanced and there was a relative skewing toward production of sCD23. These studies implicate the CD40 receptor in the hyperproduction of CD23 and sCD23 in atopic disease and suggest that abnormalities may exist in the cellular pathways leading to sCD23 production.     

Intractable pruritus in HIV infection: immunologic characterization

BACKGROUND: Severe, intractable pruritus, often associated with erythematopapular skin lesions and hypereosinophilia, is a condition observed in some nonatopic, HIV-infected patients. We performed immunovirologic analyses of this condition. METHODS: Immunologic (mitogen-stimulated production of cytokines, tumor necrosis factor-alpha [TNF-alpha], and soluble CD23; serum levels of soluble CD23, ICAM-1, TNF-alpha, IgG, IgE, and IgA) and virologic (HIV viral load) parameters were analyzed in six patients with therapy-resistant pruritus. Hypereosinophilia was present in all these patients. Results were compared to those of seven HIV-seropositive individuals similar to the first one in terms of CD4 counts and clinical staging, but without pruritus. RESULTS: Hypereosinophilia; hyper-IgE and hyper-IgA; augmented interleukin (IL)-4, IL-5, and sCD23; and reduced interferon-gamma production by mitogen-stimulated peripheral blood mononuclear cells (PBMC) were detected when patients with pruritus were compared to HIV controls. HIV viral load was also augmented in patients in whom pruritus was present. CONCLUSIONS: The results suggest that therapy-resistant, intractable pruritus accompanied by hypereosinophilia may be used to define a subset of HIV-seropositive individuals showing prototypic hyperactivation of humoral immunity, and in whom augmented HIV viral load is present.     

Elevation of soluble CD23 in sera from patients with infectious mononucleosis

CD23 is induced in B cells upon infection by Epstein-Barr virus (EBV) and a soluble form (soluble CD23: sCD23) is found in culture supernatants from EBV-transformed B cell lines. Based on these observations, we measured serum sCD23 levels in patients with infectious mononucleosis (IM) caused by EBV infection. Sera from patients with IM at the time of diagnosis contained more sCD23 than sera from normal control subjects. Changes in serum sCD23 levels during the course of disease showed that serum sCD23 levels were elevated at the time of diagnosis and they decreased to the normal levels during the convalescent phase defined by the improvement of symptoms of IM. These results indicate that the elevated levels of sCD23 were observed at the acute phase of IM and may be useful in diagnosing IM. J. Med. Virol. 53:384–387, 1997. © 1997 Wiley-Liss, Inc.     

Interleukin 5 enhances interleukin 4-induced IgE production by normal human B cells. The role of soluble CD23 antigen

Interleukin 4 (IL 4)-induced IgE production by peripheral blood lymphocytes and tonsil cells from normal donors was enhanced in a dose-dependent fashion by IL 5. IL 5 tested alone was not effective. The synergistic effects of IL 5 were most pronounced at suboptimal IL 4 concentrations, whereas at saturating IL 4 concentrations (200-300 U/ml), IL 5 had no effect. Interferon-gamma (IFN-gamma) and F(ab')2 fragments of monoclonal antibody 25 directed against the CD23 antigen, that blocked IL 4-induced IgE synthesis, also inhibited the production of IgE in the presence of combinations of IL 4 and IL 5, indicating that IL 5 potentiates the activation pathway through which IL 4 induces IgE production. In contrast, IL 4 (50 U/ml) blocked IL 5-induced IgA synthesis. IL 5 was ineffective in inducing the release of soluble CD23 (sCD23), but in the presence of IL 4 an enhanced release of sCD23 was observed, provided IL 4 was present at suboptimal concentrations. IFN-gamma completely blocked sCD23 release induced by IL 4 and IL 5. These results demonstrate that there is a strong quantitative correlation between sCD23 release and induction of IgE synthesis. sCD23 fraction-correlation between sCD23 release and induction of IgE synthesis. sCD23 fractionated from the Epstein-Barr virus-transformed B cell line RPMI 8866 was ineffective in inducing IgE production. However, sCD23 acted synergistically with suboptimal concentrations of IL 4. sCD23 did not modulate the IgE response at saturating concentrations of IL 4. Collectively, these data indicate that sCD23 plays an important regulatory role in the modulation of IL 4-induced IgE synthesis mediated by IFN-gamma and IL 5.     

T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies

Interleukin‐2 (IL‐2) is one of the most studied cytokines driving T‐cell proliferation, activation and survival. It binds to the IL‐2 receptor consisting of three chains, the α (CD25), β and common γ (γc). The binding of the CD25 chain to IL‐2 is necessary to expose high‐affinity binding sites for the β and γc chains, which, in turn, are responsible for downstream signalling. A high level of soluble CD25 (sCD25) has been associated with a poor prognosis in patients with non‐Hodgkin’s lymphoma. The function and source of origin of this soluble receptor is not well investigated. In the present study we hypothesized that T regulatory (Treg) cells may release CD25 to act as a decoy receptor for IL‐2, thereby depriving T‐effector cells of IL‐2. Peripheral blood from patients with B‐cell malignancies (n = 26) and healthy controls (n = 27) was investigated for the presence and function of FoxP3⁺ Treg cells and sCD25 by multi‐colour flow cytometry and enzyme‐linked immunosorbent assay. Further, the proliferative capacity of T cells was evaluated with or without the presence of recombinant sCD25. The results demonstrate that Treg cells from patients had lower CD25 expression intensity and that they released CD25 in vitro. Further, high levels of Treg cells correlated with sCD25 plasma concentration. Recombinant sCD25 could suppress T‐cell proliferation in vitro. In conclusion, the release of sCD25 by Treg cells may be a mechanism to deprive IL‐2 and thereby inhibit anti‐tumour T‐cell responses.     

Increased proportions of B cells with spontaneous production of interleukin‐10 in HIV‐infected individuals are normalized during combination antiretroviral therapy: a longitudinal study

Interleukin‐10 (IL‐10)‐producing B cells (B10 cells) may inhibit HIV‐specific T cells and are elevated in untreated HIV infection. We aimed to determine the effect of combination antiretroviral treatment (cART) on the proportion of B10 cells. Furthermore, we compared B10‐cell proportions in HIV‐infected progressors and viremic controllers. This was a prospective study including HIV‐infected progressors, viremic controllers and healthy controls. Progressors initiating cART were followed for 6 months. Purified B cells were stimulated with CpG, alone or in combination with HIV gp120, and the proportion of B10 cells was measured by flow cytometry. Without stimulation, the B10‐cell proportion was higher in progressors than in healthy controls, while viremic controllers and healthy controls had comparable proportions. Moreover, the proportion of CD24^hiCD38^hi transitional B cells was higher in progressors than in healthy controls. After initiation of cART, the proportion of B10 cells and transitional B cells decreased. In conclusion, progressors had elevated B10‐cell proportions, while viremic controllers displayed normal proportions. After initiation of cART, the B10‐cell proportion decreased. This could limit B10‐cell‐mediated suppression of specific CD8⁺ T‐cell responses.     

Myeloid and lymphoid activation markers in AIDS and non-AIDS presenters

HIV infection is characterized by a state of chronic activation of the immune system, which is not completely reversed by antiretroviral treatment (ART). The aim of this study was to assess myeloid and lymphoid activation markers during HIV infection, before and one year after ART initiation, in AIDS and non-AIDS presenters. Treatment naïve HIV positive patients were enrolled in this study. Myeloid dendritic cell (mDC), plasmacytoid dendritic cell (pDC), slanDC, monocyte and T-lymphocyte cell counts and activation status, were assessed by flow cytometry in peripheral blood samples. Soluble (s)CD14 and sCD163 were assessed in plasma samples using ELISA assays. Statistical analyses were performed using GraphPad Prism and Minitab Express.Thirty-four ART naïve HIV-1 infected subjects were enrolled in this study (22 non-AIDS and 12 AIDS presenters). Seventeen healthy donors (HD) were included as control group. Although circulating mDC levels resulted unchanged, HLA-DR expression was decreased on mDCs of HIV positive subjects compared to HD (p?<?0,0001). AIDS presenters showed the lowest level of expression of HLA-DR on mDCs. Circulating levels of pDCs were decreased in HIV patients compared to HD (p?<?0,001), without any changes in HLA-DR expression. SlanDC cell counts were extremely reduced in AIDS presenters, compared to non-AIDS presenters and HD (p?<?0,01 and p?<?0,0001, respectively) and showed higher HLA-DR expression in HIV patients compared to HD (p?<?0,01). Intermediate monocyte (IM) cell counts were increased in AIDS and non-AIDS presenters compared to HD (p?<?0,001 and p?<?0,001 respectively). Furthermore, IM expansion was directly correlated to HIV viral load (p?=?0,036) and independent from CD4 cell counts and activation levels. Plasma concentrations of sCD14 and sCD163 resulted increased in HIV infected subjects compared to HD (p?<?0,0001 and p?<?0,001), with the highest levels observed in AIDS presenters. After 1?year, ART was able to increase pDC and decrease IM absolute cell counts and modify HLA-DR expression on mDCs and slanDCs, approaching the levels observed in HD. ART reduced also CD4 and CD8 activation levels. In conclusion, in untreated HIV infected subjects circulating dendritic cells resulted altered either in numbers or in HLA-DR expression, especially in AIDS presenters. IM absolute counts were equally increased in AIDS and non-AIDS presenters. ART was able to reduce myeloid and lymphoid inflammation in both advanced and non-advanced HIV patients, confirming the role of ART in hampering disease progression and immune activation associated non-AIDS events.