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F Miedema

Publications and source records attributed to F Miedema.

At least 145 records · Page 8Linked to original sources
PubMed1992

Programmed death of T cells in HIV-1 infection.

In human immunodeficiency virus (HIV) infection, functional defects and deletion of antigen-reactive T cells are more frequent than can be explained by direct viral infection. On culturing, both CD4+ and CD8+ T cells from asymptomatic HIV-infected individuals died as a result of programmed cell death (apoptosis). Apoptosis was enhanced by activation with CD3 antibodies. Programmed cell death, associated with impaired T cell reactivity, may thus be responsible for the deletion of reactive T cells that contributes to HIV-induced immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1992

The CD27- subset of peripheral blood memory CD4+ lymphocytes contains functionally differentiated T lymphocytes that develop by persistent antigenic stimulation in vivo.

On the basis of expression of the T cell differentiation antigen CD27, human peripheral blood CD4+ memory cells can be divided into two subsets, a large CD45RA-CD27+ (82%) and a small CD45RA-CD27- (18%) population. Analysis of the functional properties of these memory T cell subsets showed that proliferative responses to the recall antigen tetanus toxoid (TT), shortly after booster immunization, were mainly confined to the CD27- population. Also, in atopic individuals, proliferative responses to allergens for which these individuals are sensitized, were limited to the CD45RA-CD27- population. After stimulation with CD3 monoclonal antibody and phorbol ester, CD27+ cells produced vast amounts of interleukin (IL)-2 but minimal amounts of IL-4, whereas in marked contrast, CD27- T cells secreted low levels of IL-2 and high levels of IL-4. The capacity of the vast majority of these latter cells to produce IL-4 was found to be a stable feature since high IL-4 secreting T cell clones were generated from the CD27- subset. These findings suggest that upon renewed as well as chronic antigenic stimulation in vivo, memory T cells acquire the CD45RA-CD27- phenotype and that, as a consequence, in this subset functionally differentiated CD4+ T cells are compartmentalized. Our results predict that analysis of the small CD27- subset of memory cells, that makes up approximately 10% of the peripheral blood T cell population, will provide information on the specificity and function of responding CD4+ T cells at a given point in time in healthy and diseased individuals.

Antigens↗
PubMed1992

HLA class I and II molecules present influenza virus antigens with different kinetics.

Human leukocyte antigen (HLA) class I and class II molecules differ with respect to their intracellular pathways and the compartments where they associate with processed antigen. To study possible consequences of these differences for the kinetics of antigen presentation by HLA class I and class II molecules, we analyzed changes in the concentrations of free intracellular calcium ions in influenza virus-specific T cell clones after recognition of specific antigen/HLA complexes. HLA class II-restricted viral antigen presentation by Epstein-Barr virus-transformed B lymphoblastoid cell lines (B-LCL) to CD4+ T cell clones started within 1 h and showed little variability, irrespective of antigen specificity or restriction element tested. In contrast, kinetics of viral antigen presentation by HLA class I molecules to CD8+ T cell clones were slower and differed for three antigen/HLA class I complexes tested. While B-LCL presented antigen by HLA-A2 and by HLA-B37 after at least 2 h, they only started to present antigen in the context of HLA-B7 after more than 4 h. This difference in kinetics did not correlate with differences in bulk transport rates of HLA-A2, HLA-B37, and HLA-B7, but seemed greatly influenced by differential rates of peptide generation. Brefeldin A treatment of B-LCL showed for both HLA class I and class II that de novo synthesized HLA molecules were involved in antigen presentation. Thus, differences between intracellular pathways of HLA class I and class II molecules may result in different kinetics of antigen presentation.

Antigens, Viral↗
PubMed1992

Effects of HIV-1 Tat protein on human T cell proliferation.

In inducing immunodeficiency in human immunodeficiency virus (HIV)-1 infection, a role for the HIV-1 Tat protein has been suggested. In addition to effects on viral transcription, the protein has been ascribed immunosuppressive functions, which were investigated in this study. Proliferation of purified T cells to CD3 monoclonal antibodies immobilized to plastic plates was inhibited up to 70% by addition of 5 micrograms/ml of the Tat protein. This inhibitory effect, however, was not observed in the presence of accessory cells. Furthermore, no effect of Tat protein could be observed on T cell proliferative responses to recall antigen which most likely is related to the presence of accessory cells in the cultures. Taken together, our results do not imply an important role for immunosuppressive effects of Tat in induction of immunodeficiency as observed in HIV infection in vivo.

Antigen-Presenting Cells↗
PubMed1992

Differential tropism of clinical HIV-1 isolates for primary monocytes and promonocytic cell lines.

Previously we demonstrated a correlation between a nonsyncytium-inducing (NSI), non-T-cell line tropic phenotype of HIV-1 isolates and the capacity to replicate in primary monocyte-derived macrophages (MDM). Here we demonstrate that these NSI, monocytotropic HIV-1 isolates lack the capacity to replicate in two promonocytic cell-lines, HL60 and U937. In contrast, most syncytium-inducing (SI) HIV-1 isolates with tropism for T-cell lines and generally non-monocytotropic were able to establish a productive infection in promonocytic cell lines. Similar differences in tropism for monocytes and promonocytic cell lines were observed with infectious molecular clones. Our results indicate that virological studies on promonocytic cell lines do not necessarily pertain to the HIV-1 infection of monocytes in vivo.

Cell Line↗
PubMed1992

Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection.

Nineteen individuals were studied for virologic and immunologic events during primary human immunodeficiency virus type 1 (HIV-1) infection. In 16 individuals only non-syncytium-inducing (NSI) isolates were detected; syncytium-inducing (SI) isolates were obtained from 3. Studies of transmitter-recipient pairs indicated that both NSI variants and SI variants were transmitted and that SI variants may be suppressed in the recipient. CD4+ T cells remained in the normal range in 15 of 16 individuals with NSI isolates but rapidly declined in all 3 individuals with SI variants, 1 of whom was treated with zidovudine. The most marked increase in CD8+ T cells and activated CD8+ T cells was observed in individuals with the most pronounced clinical signs of acute HIV-1 infection. Activated CD8+ T cells were only transiently elevated in individuals with SI variants, suggesting that an impaired cellular anti-HIV-1 immune response plays a role in the rapid progression to AIDS.

CD4-Positive T-Lymphocytes↗
PubMed1992

HIV-1 biological phenotype in long-term infected individuals evaluated with an MT-2 cocultivation assay.

OBJECTIVE: We have previously demonstrated that detection of syncytium-inducing (SI) HIV-1 in asymptomatic seropositive individuals is associated with rapid progression to AIDS. In the present study, we sought to develop and evaluate an HIV-1 phenotyping assay for the screening of large numbers of individuals. METHODS: Efficiency of HIV-1 isolation from patient peripheral blood mononuclear cells (PBMC) was studied with donor PBMC or seven different CD4+ T-cell lines as target cells. The biological phenotype of sequential isolates from 20 long-term asymptomatic HIV-1-seropositive individuals was determined by two different assays. RESULTS: Non-SI isolates, efficiently recovered by cocultivation with donor PBMC, were never isolated with T-cell lines as target cells. Direct cocultivation with MT-2 cells, but not with six other CD4+ T-cells, resulted in the efficient recovery of SI isolates. HIV-1 MT-2 tropism and SI capacity were shown to be coupled properties at the clonal level. SI isolates emerged in 10 out of 20 longitudinally-studied individuals. In these long-term infected individuals, appearance of SI isolates was associated with progression to AIDS. CONCLUSIONS: Direct cocultivation of patient PBMC with the MT-2 cell line is a sensitive, specific and convenient method to detect SI isolates. The availability of an assay suitable for the screening of large groups allows further study of the value of HIV-1 biological phenotyping as a prognostic marker.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Biphasic rate of CD4+ cell count decline during progression to AIDS correlates with HIV-1 phenotype.

OBJECTIVE: To determine the kinetics of decline of CD4+ lymphocytes in HIV-1-infected asymptomatic homosexual men. METHODS: CD4+ lymphocytes were enumerated in a cohort of 187 HIV-1-infected initially asymptomatic homosexual men seen at 3-month intervals over 5 years. During follow-up, 45 men progressed to AIDS (excluding cases presenting with Kaposi's sarcoma). Correlation between rate of CD4+ cell decline and presence of a particular HIV-1 biological phenotype was analysed in 43 participants. RESULTS: CD4+ cell counts declined slowly and continuously in HIV-1-seropositive men who remained asymptomatic during follow-up. A biphasic CD4+ cell count decline was observed in the group who developed AIDS: the decline was slow and steady (5.6 x 10(6)/l per month, similar to that observed in the asymptomatic group) until 18 months before AIDS diagnosis, but became three to five times faster thereafter. Rapid CD4+ cell decline was significantly related to syncytium-inducing, fast-replicating HIV-1 isolates; during the period of slow and steady CD4+ cell count decline, non-syncytium-inducing isolates were predominant. CONCLUSIONS: At an average of 18 months preceding AIDS diagnosis, a three to fivefold increase in the rate of loss of CD4+ lymphocytes occurs, and may be related to the appearance of a more virulent HIV-1 phenotype.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Biological phenotype of human immunodeficiency virus type 1 clones at different stages of infection: progression of disease is associated with a shift from monocytotropic to T-cell-tropic virus population.

The composition of human immunodeficiency virus type 1 (HIV-1) clonal populations at different stages of infection and in different compartments was analyzed. Biological HIV-1 clones were obtained by primary isolation from patient peripheral blood mononuclear cells under limiting dilution conditions, with either blood donor peripheral blood lymphocytes or monocyte-derived macrophages (MDM) as target cells, and the biological phenotype of the clones was analyzed. In asymptomatic individuals, low frequencies of HIV-1 clones were observed. These clones were non-syncytium inducing and preferentially monocytotropic. In individuals progressing to disease, a 100-fold increase in frequencies of productively HIV-1-infected cells was observed as a result of a selective expansion of nonmonocytotropic clones. In a person progressing to AIDS within 19 months after infection, only syncytium-inducing clones were detected, shifting from MDM-tropic to non-MDM-tropic over time. From his virus donor, a patient with wasting syndrome, only syncytium-inducing clones, mostly non-MDM-tropic, were recovered. Parallel clonal analysis of HIV-1 populations in cells present in bronchoalveolar lavage fluid and peripheral blood from an AIDS patient revealed a qualitatively and quantitatively more monocytotropic virus population in the lung compartment than in peripheral blood at the same time point. These findings indicate that monocytotropic HIV-1 clones, probably generated in the tissues, are responsible for the persistence of HIV-1 infection and that progression of HIV-1 infection is associated with a selective increase of T-cell-tropic, nonmonocytotropic HIV-1 variants in peripheral blood.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Phenotype-associated sequence variation in the third variable domain of the human immunodeficiency virus type 1 gp120 molecule.

The third variable (V3) domain has been implicated in determining the human immunodeficiency virus (HIV) phenotype, including fusion capacity and monocytotropism. In a large set of primary HIV type 1 (HIV-1) isolates, V3 sequence analysis revealed that fast-replicating, syncytium-inducing isolates contained V3 sequences with a significantly higher positive charge than those of slow-replicating, non-syncytium-inducing monocytotropic isolates. It appeared that these differences in charge could be attributed to highly variable amino acid residues located on either side of the V3 loop, midway between the cysteine residues and the central GPG motif. In non-syncytium-inducing monocytotropic isolates, these residues were negatively charged or uncharged, whereas in syncytium-inducing nonmonocytotropic isolates, either one or both were positively charged. The substitutions at these positions result in changes in the predicted secondary structure of the V3 loop. Our data suggest that two amino acid residues in the highly variable V3 domain are responsible for phenotype differences and point to conformational differences in V3 loops from phenotypically distinct HIV-1 isolates.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Proliferation-dependent HIV-1 infection of monocytes occurs during differentiation into macrophages.

Requirements for the establishment of productive infection with the human immunodeficiency virus type 1 (HIV-1) in primary monocytes were investigated. In vitro, monocytes rendered susceptible for infection after at least a 2-d culture, but when cultured in the presence of differentiation-inducing agent IL-4, accelerated susceptibility was seen. Complete resistance to HIV-1 infection was observed in monocytes that had been treated for 5 d with rIL-4, and comparable results were obtained with other differentiation inducers such as dexamethasone or 1,25(OH)2 vitamin D3 (1,25(OH)2vitD3). The inhibition of productive infection was not caused by downregulation of CD4 expression or HIV-1 transcription, nor by intracellular accumulation of virions. Since treatment with rIL-4, dexamethasone, or 1,25(OH)2vitD3 also resulted in complete inhibition of monocyte proliferation, we studied whether establishment of productive infection in monocytes is proliferation dependent. Irradiation or mitomycin-C treatment within 24 h after inoculation prevented productive HIV-1 infection of monocytes, suggesting a proliferation-dependent step early in the virus replication cycle. Polymerase chain reaction (PCR) analysis revealed the presence of only incomplete proviral DNA species in non-proliferating monocytes, indicating restriction of viral replication at the level of reverse transcription. Thus, in analogy with HIV-1 infection of CD4+ T cells, proliferation of monocytes during differentiation into macrophages is a prerequisite for productive infection with HIV.

Base Sequence↗
PubMed1992

Immunological abnormalities in the natural history of HIV infection: mechanisms and clinical relevance.

Infection with the human immunodeficiency virus (HIV) ultimately results in profound immunodeficiency characterized by severe depletion of CD4+ T helper cells. In symptomatic infection a general perturbance of immune function is observed. Here recent insights in the sequence of events in progression to AIDS is reviewed. Following seroconversion a rapid persistent loss of inducible B cell function is observed. In addition, in long term infection, antigen-presenting cell functions of monocytes and dendritic cells are increasingly affected. T-cell non-responsiveness, preceding CD4 cell loss, appears to be induced through several different, sequential mechanisms. In early infection, the in-vivo deletion of memory cells can account for the in-vitro decreased responsiveness. Later on in infection, when the balance between memory and naive T cells is normalized, both CD4 and CD8 cells are non-responsive to nominal antigen and low dose anti-CD3 monoclonal antibodies. This anergy is at the level of IL-2 gene expression since early signal transduction events following CD2 and CD2 receptor occupancy are normal. This state of anergy, probably due to inappropriate activation in vivo, may be related to programmed cell death (PCD) observed in vitro for both CD8 and CD4 cells reflecting a systemic interference with maturation and differentiation of T cells. In progression to symptomatic infection, the proportion of non-responsive CD8 cells with immature or activated phenotypes increases and in about fifty percent of the cases, CD4 cell decline may accelerate in association with emergence of syncytium-inducing HIV variants. During this progressive stage, anti-CD3 reactivity is severely decreased, and alloantigen reactivity and finally the capacity to respond to phytohemagglutinin (PHA) are affected. These functional parameters appear useful for staging of HIV-infected individuals and for evaluation of anti-viral therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Human CD8+ T lymphocytes can be divided into CD45RA+ and CD45RO+ cells with different requirements for activation and differentiation.

The functional distinction between CD45RA+ and CD45RO+ cells within the human CD4+ T cell subset is well established. This study was undertaken to investigate whether a similar division can be made within the CD8+ T cell population. A quantitative comparison was made of the requirements for activation and differentiation of CD8+CD45RA+ and CD8+CD45RO+ cells. Stimulation of T lymphocytes with anti-CD3 mAb immobilized at high-density induced strong proliferation and CTL activity in both CD45RA+ and CD45RO+ cells. Suboptimal TCR/CD3 triggering, in contrast, induced substantially higher levels of proliferation and CTL activity in CD8+CD45RO+ cells compared with their CD45RA+ counterparts. Lymphokine secretion (i.e., Il-2 and TNF-alpha) was under any condition more readily induced in CD8+CD45RO+ cells. Markedly, proliferation of both CD8+CD45RA+ and CD8+CD45RO+ T cells initiated by anti-CD3 mAb immobilized at high densities was not inhibited by addition of anti-CD25 mAb, in contrast to proliferation induced by suboptimal anti-CD3 mAb concentrations. These findings show that a functional division between CD45RA+ and CD45RO+ T cells with distinct requirements for activation and differentiation may also be made in the CD8+ subset.

Antigens, CD↗
PubMed1991

Non-mitogenic T cell activation signals are sufficient for induction of human immunodeficiency virus transcription.

The expression of human immunodeficiency virus type 1 (HIV) is enhanced after T cell activation due to the interaction of cell-encoded nuclear factors with binding sites in the viral long terminal repeats (LTR). We studied the minimal signal transduction requirements for induction of HIV transcription during T cell activation. Monoclonal antibodies (mAb) against the T cell receptor/CD3 complex induced interleukin (IL) 2 production as well as HIV-LTR-directed gene expression in Jurkat T cells. Addition of cyclosporin A or buffering of intracellular Ca2+ changes did not abolish this LTR-directed gene expression but did block IL 2 production. In contrast, interference with protein kinase C (PKC) activation did inhibit both IL 2 production and LTR-driven gene expression. Under all conditions HIV-LTR-directed gene expression correlated with gene expression induced by the NF-kB binding enhancer, but not by the NF-AT or OCT-1 binding sites. In accordance with observations by Verweij, Geerts and Aarden on the CD28 co-stimulatory activation of IL2 transcription via an NF-kB-like activity, stimulation of the CD2, CD28 and CD44 accessory molecules was tested to mimick physiological activation signals independent of T cell receptor triggering. mAb directed against CD2 and CD44 only marginally induced the LTR. Next, non-mitogenic stimulation by mAb against CD28 clearly induced the HIV-LTR- and NF-kB- but not NF-AT- and OCT-1-driven chloramphenicol acetyltransferase CAT expression, showing a direct effect on gene expression via this receptor. Taken together, this report shows that non-mitogenic T cell activation signals are sufficient to induce HIV transcription. The finding that these signals may be delivered by receptors that are not dependent on antigen-specific activation may have important implications for our understanding of HIV pathogenesis.

Antigens, CD↗
PubMed1991

Allo-cross-reactivity of a human neuraminidase-specific T cell clone dependent on presentation of an endogenous B cell-specific antigen.

T cells specific for foreign antigen recognize a complex of peptides and self-major histocompatibility complex (MHC) molecules and can also cross-react with allo-MHC molecules. It remains controversial, however, what alloreactive T cells exactly recognize. It has been proposed that alloreactive T cells recognize endogenous peptides presented by allo-MHC molecules. To test this hypothesis, we examined an influenza virus-specific T cell clone (6H5), specific for neuraminidase N2 and restricted by HLA-DR1. In the absence of influenza virus, this clone cross-reacted with HLA-DR1Dw1+ but not with HLA-DR1Dw20+ Epstein-Barr virus-transformed lymphoblastoid cells (B-LCL). Cold target inhibition experiments and the rearrangement pattern of the T cell receptor beta chain indicated that 6H5 was a monoclonal T cell population most likely using the same T cell receptor for both responses. To determine whether determinants other than HLA-DR1Dw1+ B-LCL or activated B cells, but, surprisingly, not to other cell types expressed HLA-DR1Dw1, including monocytes and transfected L cells. These experiments further support the concept that recognition of allogeneic MHC (in this case HLA-DR1Dw1) may result from a cross-reactivity of T cells specific for a complex of foreign antigen and self-MHC (neuraminidase N2 and HLA-DR1Dw20). Furthermore, allorecognition of T cell clone 6H5 appears to depend upon the recognition of a complex of allogeneic MHC and a cell-type specific endogenous peptide presented by activated B cells.

Antigens, Surface↗
PubMed1991

Frequent injecting impairs lymphocyte reactivity in HIV-positive and HIV-negative drug users.

To investigate whether drug use affected immunological parameters, we conducted a cross-sectional study of 321 drug users. Absolute numbers of CD4+ lymphocytes and the T-cell reactivity were lower in HIV-positive than in HIV-negative people. The functional capacity of the T-cell system as measured after stimulation with a monoclonal antibody directed against CD3 was found to be strongly associated with the frequency of injecting, while no relationship was found between the frequency of injecting and the total number of lymphocytes or T-cell subsets. HIV-negative and HIV-positive drug users who had injected a mean of three times a day in the preceding 4-6 months had a T-cell reactivity which was 40-50% lower compared with seronegative and with seropositive drug users who had not injected in the preceding months. We conclude that lymphocyte reactivity is depressed by frequent injecting in HIV-negative and HIV-positive drug users.

Adult↗
PubMed1991

Differences in clinical course in zidovudine-treated asymptomatic HIV-infected men associated with T-cell function at intake.

Declining CD4+ T-cell numbers and anti-CD3-induced T-cell responsiveness are prognostic markers for progression of HIV infection. We investigated the effect of long-term (2-year) zidovudine treatment on these immunological markers in a group of nine asymptomatic p24-antigenaemic men, five of whom progressed to AIDS. A group of 10 untreated HIV-infected men, five of whom progressed to AIDS, was studied as a control. At intake, 1 year before the start of treatment, CD4+ T-cell numbers in the groups were not significantly different. However, at that time progressors already exhibited an extremely low anti-CD3-induced T-cell responsiveness compared with non-progressors. In all people T-cell responsiveness and the number of CD4+ T-cells had improved 6 months after the start of zidovudine treatment. However, CD4+ T-cell numbers were not persistently elevated, and restoration of T-cell responsiveness was of only short duration. Our results show that zidovudine treatment in the asymptomatic phase of HIV infection did not result in a sustained improvement in T-cell function. Furthermore, they suggest that differences in clinical course among zidovudine-treated asymptomatics may be caused by heterogeneity of this group with respect to T-cell functional capacity at the start of treatment.

Acquired Immunodeficiency Syndrome↗