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Biomedical subjects

F Chiodi

Publications and source records attributed to F Chiodi.

At least 19 recordsLinked to original sources
PubMed2002

Plasma levels of soluble CD27: a simple marker to monitor immune activation during potent antiretroviral therapy in HIV-1-infected subjects.

Plasma levels of soluble CD27 (sCD27) are elevated in diseases characterized by T cell activation and are used as a marker of immune activation. We assessed the usefulness of determining plasma sCD27 as a marker for monitoring immune activation in HIV-1-infected patients treated with highly active antiretroviral therapy (HAART). A first cross-sectional examination of 68 HIV-1-infected and 18 normal subjects showed high levels of sCD27 in HIV-1 infection; plasma sCD27 was correlated to HIV-1 viraemia and inversely correlated to CD4+ T cell count. Twenty-six HIV-1-infected patients undergoing HAART were studied at baseline and after 6, 12, 18 and 24 months of therapy. Seven additional patients under HAART were analysed at baseline, during and after interruption of therapy. In the total population, HAART induced a significant and progressive reduction, but not a normalization, of plasma levels of sCD27 after 24 months. A full normalization of plasma sCD27 was observed in the virological responders (undetectable HIV-1 RNA at months 18 and 24) and also in patients with moderate immunodeficiency at baseline (CD4+ T cell count >200 cells/mm3). Changes in plasma neopterin paralleled the changes in sCD27 but only baseline sCD27 levels were predictive of a greater increase in CD4+ T cell count during the follow-up. Discontinuation of therapy resulted in a rapid increase of sCD27 plasma levels associated with viraemia rebound and drop in CD4+ T cell count. Our findings suggest that plasma sCD27 may represent an alternative and simple marker to monitor immune activation during potent antiretroviral therapy. HIV-1-induced immune activation can be normalized by HAART in successfully treated patients where the disease is not advanced.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Alteration of Fas and Fas ligand expression during human visceral leishmaniasis.

Several studies in murine systems have suggested a role of apoptosis in the pathogenesis of leishmaniasis. However, the role of apoptosis in visceral leishmaniasis in man has not been explored. In this study, we show that patients with visceral leishmaniasis demonstrate significant dysregulation of Fas and Fas ligand. Levels of soluble Fas (sFas) and soluble Fas ligand (sFasL) were elevated in plasma of patients with active visceral leishmaniasis (VL) and individuals co-infected with VL-HIV-1 compared to healthy controls. The levels of sFas and sFasL were normalized 6 months after successful treatment. In VL patients, the expression of membrane bound Fas, and to a lower extent FasL, were up-regulated on Leishmania donovani-infected spleen cells, the site of parasite multiplication. Expression of Fas and FasL on peripheral blood mononuclear cells was within normal range, probably reflecting that the blood is not a normal site of L. donovani infection. Furthermore, this is suggested by the finding that in vitro infection of macrophages with L. donovani up-regulated Fas expression on the surface of infected cells and enhanced the levels of sFasL in supernatants from infected cultures. How this dysregulation may affect the pathogenesis of human visceral leishmaniasis is discussed.

Animals↗
PubMed2001

Soluble CD23 in cerebrospinal fluid: a marker of AIDS-related non-Hodgkin's lymphoma in the brain.

BACKGROUND: AIDS-related non-Hodgkin's lymphoma (NHL) includes systemic lymphomas, often with brain involvement, and primary central nervous system (CNS) lymphomas. OBJECTIVE: To examine if measurement of soluble CD23 (sCD23) in cerebrospinal fluid (CSF) is useful in the diagnosis and follow-up of AIDS-related NHL. METHOD: sCD23 was measured by enzyme-linked immunosorbent assay and EBV DNA by nested polymerase chain reaction for a group of 134 patients. The NHL group included 14 patients with primary HIV-1 CNS lymphoma, 12 patients with brain involvement of systemic HIV-1 NHL and 10 patients with systemic HIV-1 NHL without brain involvement. These were compared with HIV-1-infected patients with cerebral toxoplasmosis (19), progressive multifocal leukoencephalitis (PML; 8) and AIDS-related dementia (17) and with asymptomatic HIV-1 carriers (54) and uninfected individuals (50). The levels of sCD23 were compared with the presence of Epstein-Barr virus (EBV) DNA in CSF. RESULTS: Significantly higher levels of sCD23 were found in the CSF of the patients with brain lymphoma than in those with systemic NHL (P < 0.002) or with cerebral toxoplasmosis, PML and AIDS-related dementia (P < 0.0001). The sensitivity and specificity of sCD23 in CSF as a marker for detection of brain NHL were 77% and 94%, respectively. High levels of sCD23 were found in CSF from patients with brain NHL independently of the presence (18 out of 26) or absence (8 out of 26) of EBV DNA. CONCLUSIONS: The sCD23 in CSF of HIV-1-infected patients may represent an additional, non-invasive marker for diagnosis of brain involvement in AIDS-related NHL.

Biomarkers↗
PubMed2001

Loss of memory (CD27) B lymphocytes in HIV-1 infection.

OBJECTIVES: The mechanisms of B-cell dysfunction during HIV-1 infection, including polyclonal B-cell activation, are poorly understood. We studied the phenotype and the functionality of peripheral memory B cells in HIV-1-infected subjects. DESIGN: The phenotype of B cells and the responsiveness to T-cell dependent activation in vitro were analysed in 36 HIV-1-infected and 34 healthy subjects. METHODS: Phenotyping of B and T cells was performed by FACS. IgG content was measured in plasma (by nephelometry) and cultures (by enzyme-linked immunosorbent assay) of B lymphocytes activated through CD40 or CD27 ligation. Expression of Fas and Fas ligand was performed by FACS on B-cell subpopulations from five HIV-1-infected and four uninfected subjects. RESULTS: The peripheral memory (CD27) B cells were significantly reduced in HIV-1-infected subjects. The amount of memory B cells was low in both drug-naive subjects and patients undergoing antiretroviral therapy. Ex vivo expression of CD70 (CD27 ligand) on T cells was significantly higher in HIV-1-infected subjects and inversely correlated with the frequency of memory B cells. In spite of the reduced number of memory B cells, in vitro spontaneous and activation-induced IgG secretion was higher in HIV-1-infected patients than in uninfected controls. The hyperactivation status of B lymphocytes in HIV-1-infected patients was further confirmed by the finding of upregulation of Fas and FasL expression on memory B cells. CONCLUSIONS: Memory B lymphocytes are depleted from peripheral blood in HIV-1-infected subjects. Our ex vivo findings suggest that persistent T-cell activation may contribute to loss of memory B cells through upregulation of Fas/FasL on these cells and terminal differentiation into plasma cells.

Antibodies, Monoclonal↗
PubMed2001

Elevated levels of soluble Fas and Fas ligand in cerebrospinal fluid of patients with AIDS dementia complex.

We measured the levels of sFas and sFasL in CSF and serum of HIV-1 infected patients and related them to AIDS dementia complex (ADC). Specimens were obtained from 51 HIV-1 infected individuals (29 with ADC) and 39 HIV negative individuals. The sFas was detectable in all sera and 98% of CSF specimens. Measurable levels of sFasL were found in 79% of the CSF and 98% of sera samples. According to the presence or absence of ADC, we observed significant differences in CSF sFas (median and IQR 116, 132 vs. 30, 23 pg/ml, P<0.001) and sFasL (median and IQR 127, 290 vs. 15, 73 pg/ml, P<0.001) levels. The sFas in serum differed significantly between HIV-1 infected subjects and non-infected controls (P<0.001), with no correlation to ADC. On the contrary, sFasL in serum differed among HIV-1 infected subjects according to clinical signs of ADC. In the cross-sectional study, the number of cells present in CSF and CD4+ T cell counts in blood did not correlate to the levels of CSF sFas and sFasL. Interestingly, the number of HIV RNA copies in CSF correlated significantly to the levels of CSF sFasL (P=0.001) but not to sFas in the same compartment. Antiretroviral therapy reduced viral load and sFas levels in CSF in the majority of patients. sFas is a useful marker for ADC diagnosis and follow-up during antiviral treatment.

AIDS Dementia Complex↗
PubMed2000

[Cytostatic therapy reduces the immune defense. Children treated for leukemia have impaired immunity against measles and rubella].

A study is summarized analyzing the levels of serum antibodies against vaccination antigens in 43 children treated for acute lymphoblastic leukemia. Two different therapeutical regimens were used. All children had been immunized against measles and rubella before being diagnosed with leukemia. Eight of the 24 children treated 1986-1991 lacked protective levels of antibodies against measles; four of the 24 children lacked antibodies against rubella. In the second cohort of children (n = 16) treated from 1992 and onwards, nine lacked protective levels of antibodies against measles, eight lacked antibodies against rubella.

Antibodies, Viral↗
PubMed2000

High plasma levels of soluble fas in HIV type 1-infected subjects are not normalized during highly active antiretroviral therapy.

Plasma levels of soluble Fas (sFas) are elevated in human immunodeficiency virus type 1 (HIV-1) infection, indicating dysregulation of the Fas apoptosis pathway and chronic immune activation. We performed a retrospective study to investigate the effects of HAART on plasma levels of sFas. A cross-sectional study of 27 drug-naive infected subjects and 49 patients under antiretroviral treatment showed that plasma levels of sFas were higher in HIV-1-infected subjects than in 52 HIV-1-negative controls, independently of the treatment status. In a longitudinal study of 69 patients undergoing HAART, we observed a minimal, but significant decrease in sFas plasma levels after 1 year of therapy. Levels of sFas, however, remained still higher than physiologic values. Patients undergoing HAART were further classified as nonresponders or responders on the basis of viremia suppression; no significant changes in plasma levels of sFas were observed between the two groups. These findings show that 1 year of HAART has a minor effect on the sFas levels in plasma. Long-term HAART may be required to normalize the dysregulation of the Fas apoptotic pathway and the persistent immune activation initiated by HIV-1.

Anti-HIV Agents↗
PubMed1999

Nonproductive human immunodeficiency virus type 1 infection of human fetal astrocytes: independence from CD4 and major chemokine receptors.

Human immunodeficiency virus type 1 (HIV-1) infection of the brain is associated with neurological manifestations both in adults and in children. The primary target for HIV-1 infection in the brain is the microglia, but astrocytes can also be infected. We tested 26 primary HIV-1 isolates for their capacity to infect human fetal astrocytes in culture. Eight of these isolates, independent of their biological phenotype and chemokine receptor usage, were able to infect astrocytes. Although no sustained viral replication could be demonstrated, the virus was recovered by coculture with receptive cells such as macrophages or on stimulation with interleukin-1beta. To gain knowledge into the molecular events that regulate attachment and penetration of HIV-1 in astrocytes, we investigated the expression of several chemokine receptors. Fluorocytometry and calcium-mobilization assay did not provide evidence of expression of any of the major HIV-1 coreceptors, including CXCR4, CCR5, CCR3, and CCR2b, as well as the CD4 molecule on the cell surface of human fetal astrocytes. However, mRNA transcripts for CXCR4, CCR5, Bonzo/STRL33/TYMSTR, and APJ were detected by RT-PCR. Furthermore, infection of astrocytes by HIV-1 isolates with different chemokine receptor usage was not inhibited by the chemokines SDF-1beta, RANTES, MIP-1beta, or MCP-1 or by antibodies directed against the third variable region or the CD4 binding site of gp120. These data show that astrocytes can be infected by primary HIV-1 isolates via a mechanism independent of CD4 or major chemokine receptors. Furthermore, astrocytes are potential carriers of latent HIV-1 and on activation may be implicated in spreading the infection to other neighbouring cells, such as microglia or macrophages.

Adult↗
PubMed1999

Upregulated expression of Fas and Fas ligand in brain through the spectrum of HIV-1 infection.

Apoptosis of neurons and glial cells has been shown to occur in the brain of patients with the acquired immune deficiency syndrome (AIDS) and was postulated as contributing to brain atrophy and white matter damage in these patients. Since apoptotic events may be induced by the Fas-Fas ligand (FasL) system, we analyzed the relevance of these molecules to cell depletion in eight brains from HIV-1-infected patients and nine HIV-1-negative controls all of whom were analyzed histopathologically. The presence of Fas and FasL in brain tissue was analyzed by PCR amplification using Fas- and FasL-specific oligonucleotide primers and immunohistochemistry. The visualization of DNA fragmentation was used to evaluate apoptosis. Fas transcripts were detected in brains from each of four AIDS patients, each of three asymptomatic HIV-1 carriers and each of two HIV-1-negative controls. In the brains from AIDS patients the level of Fas expression was higher than in asymptomatic carriers and uninfected controls. FasL transcripts were seen in three of seven HIV-1-infected brains, two AIDS cases and one asymptomatic HIV-1 carrier. The predominant Fas-expressing cells were reactive astrocytes seen in each of two AIDS patients and one pre-AIDS case, but not in HIV-1-negative controls. Occasional Fas-positive oligodendrocyte-like cells were also seen in AIDS and pre-AIDS cases. No significant expression of Fas and FasL was seen in neurons. Fas-positive reactive astrocytes were more frequent in foci of HIV-1 encephalitis (HIVE). In the same area reactive apoptotic astrocytes were seen in close vicinity to FasL-expressing CD3 T lymphocytes, suggesting that apoptosis of astrocytes is mediated by Fas-FasL. The Fas expression on glial cells in asymptomatic HIV-1 infection may indicate apoptosis already in the asymptomatic stage of HIV-1 disease. In AIDS brains expression of Fas and FasL may contribute to the loss of glial cells and indirectly to the loss of neurons.

Acquired Immunodeficiency Syndrome↗
PubMed1998

A three-dimensional model of the Fas/APO-1 molecule: cross-reactivity of anti-Fas antibodies explained by structural mimicry of antigenic sites.

Fas/APO-1 is a member of the tumor necrosis factor (TNF)/nerve growth factor receptor family. This cell surface protein, when associated with the Fas/APO-1 ligand or specific mAb, elicits an apoptotic response in susceptible cells via an oligomerization of its intracellular domains, termed the'death domains'. We have previously mapped the epitopes of a panel of Fas/APO-1-reactive mAb to a series of linear portions of the Fas/APO-1 molecule. In order to gain a greater understanding of the mode of interaction of these antibodies with the Fas/APO-1 antigen, we constructed a homology-based model of the extracellular portion of the molecule, based on the crystallographic coordinates of the TNF type I receptor. The model clearly demonstrates that the antibodies do not identically mimic the endogenous ligand to achieve their effect, but probably act in an analogous manner by recruiting Fas/APO-1 molecules into clusters which may lead to oligomerization of 'death domains'. Moreover, the apparent cross-reactivity observed for the monoclonal anti-Fas antibodies between different linear regions of the Fas/APO-1 molecule was found to be due, most likely, to the structural mimicry of these epitopes. Reduction of the Fas/APO-1-derived cross-reactive peptides by dithiothreitol completely abrogated their antigenic reactivity with the anti-Fas mAb CH-11, thus indicating that the establishment of intrapeptide disulfide bonds is critical for antigenic reactivity.

Amino Acid Sequence↗
PubMed1998

Induction of human immunodeficiency virus type 1 replication in human glial cells after proinflammatory cytokines stimulation: effect of IFNgamma, IL1beta, and TNFalpha on differentiation and chemokine production in glial cells.

Although evidence for human immunodeficiency virus 1 (HIV-1) presence in the central nervous system (CNS) of infected patients is well established, the intensity of viral replication within the brain is not usually known. In vitro, human embryonic microglial cells internalized HIV-1 through a CD4-dependent pathway but were not permissive to viral replication. We observed that HIV replication was induced when CNS cell cultures were stimulated for 14 days by a combination of proinflammatory cytokines including IFNgamma, IL1beta, and TNFalpha. After long-term cytokine stimulation, morphologically differentiated glial cells appeared, in which HIV-1 tat antigen was detected after infection. Thus, variations in the stage of maturation/activation of CNS cells under inflammatory conditions probably play a major role in facilitating massive production of HIV-1. We then studied the effect of prolonged cytokine stimulation on the secretion of inflammatory mediators by glial cells. An early increased secretion of prostaglandin F2alpha and chemokines (RANTES>>MIP-1alpha>>MIP-1beta) was observed, due to both microglia and astrocytes. In contrast to persistent PGF2alpha production, an extinction of RANTES and MIP-1beta but not of MIP-1alpha secretion occurred during the 14 days of stimulation and was inversely correlated with the ability of glial cells to replicate HIV-1. The study of the secretory factors produced in response to a persistent inflammation could provide a better understanding of the modulation of HIV replication in glial cells.

Cell Differentiation↗
PubMed1997

Apoptosis of CD4+ and CD19+ cells during human immunodeficiency virus type 1 infection--correlation with clinical progression, viral load, and loss of humoral immunity.

Enhanced rates of programmed cell death (apoptosis) have been detected in T cells and B cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals. To evaluate the possible relevance of this event to HIV pathogenesis and disease progression, apoptosis in CD4+ T lymphocytes and CD19+ B lymphocytes, viral load, and neutralizing antibody titers were assayed in HIV-1-infected slow progressors and progressors. A correlation was found between progressive disease and apoptosis of CD4+ T cells. The extent of apoptosis in CD4+ cells was similar in slow progressors and seronegative control subjects. By contrast, we found elevated levels of B-cell apoptosis in all HIV-1-infected individuals compared with seronegative control subjects, with a tendency toward increased levels of apoptosis with progressive disease. Apoptosis in CD4+ T cells and CD19+ B cells correlated with viral RNA levels in plasma. Furthermore, higher rates of B-cell apoptosis were observed in individuals with poor neutralizing activity against a panel of six clinical HIV-1 isolates. From these results we conclude that the extent of apoptosis in cultured CD4+ cells and CD19+ cells appears to parallel the decline in CD4 cell counts in infected individuals. The finding of a relation between apoptosis in B cells and poor neutralizing capacity suggests that apoptosis may be related to loss of immune function. A role for apoptosis in the pathogenesis of AIDS is also supported by the strong correlation between viral load and rates of apoptosis in CD4+ T cells.

Antibody Formation↗
PubMed1997

Progressive B cell apoptosis and expression of Fas ligand during human immunodeficiency virus type 1 infection.

HIV-1 infection causes functional defects in T cells. It also leads to a progressive reduction in numbers of such cells and both CD4+ and CD8+ cells have been reported to undergo apoptosis in culture. A corresponding reduction in B cells has not been described, but these cells are also functionally altered, with reports of polyclonal activation and hyporesponsiveness to antigenic and mitogenic stimuli. Here we investigated B cells from HIV-1-seropositive individuals and found that these cells, which are not the target for virus infection, died of apoptosis on culturing. We could also confirm previous findings that CD4+ cells from HIV-1-infected individuals undergo apoptosis in culture. Apoptosis of both B cells and CD4+ cells correlated inversely with CD4 cell counts. B cells from HIV-1-infected individuals were found to express Fas ligand, and the expression of this protein correlated with the levels of apoptosis in the same cells. Non-B cells, on the other hand, expressed increased levels of Fas but low levels of Fas ligand. These results are in line with suggestions that the Fas/Fas ligand pathway may trigger the increased levels of apoptosis observed in cells from HIV-1-infected individuals.

Adult↗
PubMed1997

Anti-Fas IgG1 antibodies recognizing the same epitope of Fas/APO-1 mediate different biological effects in vitro.

Fas/APO-1 is a cell surface glycoprotein that mediates programmed cell death or apoptosis when cross-linked with agonistic anti-Fas or anti-APO-1 mAb or the endogenous Fas/APO-1 ligand. In this report, we examined the in vitro biological properties of a panel of anti-human Fas mAb of IgG1 subclass (ZB4, VB3, WB3 and CBE). We found that anti-Fas clone VB3 induced marked apoptotic cell death in Fas/APO-1-expressing Jurkat cells, although this cell killing was delayed when compared to the cytolytic effect mediated by the prototypic anti-Fas antibody of IgM subclass (clone CH-11). The ZB4 antibody, on the other hand, efficiently blocked apoptosis induced by CH-11. The WB3 and CBE clones neither induced or inhibited apoptosis. These antibodies were all found to recognize one and the same linear site on the Fas/APO-1 molecule, despite their different biological effects. The ability of these anti-Fas mAb to induce or inhibit apoptosis appeared to correlate with their relative affinity for the Fas/APO-1 molecule. These results provide further evidence for the potential of anti-Fas antibodies of the IgG1 subclass to elicit signals via the Fas/APO-1 molecule.

Amino Acid Sequence↗