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Biomedical subjects

F Miedema

Publications and source records attributed to F Miedema.

At least 109 records · Page 6Linked to original sources
PubMed1995

T cell function in vitro is an independent progression marker for AIDS in human immunodeficiency virus-infected asymptomatic subjects.

The predictive value of low T cell reactivity to CD3 monoclonal antibodies for development of AIDS was evaluated and compared with low CD4+ cell numbers and the presence of syncytium-inducing human immunodeficiency virus (HIV) variants in 122 seropositive asymptomatic homosexual men for 4.5 years. Low T cell reactivity was a strong predictor for progression to AIDS in a multivariate proportional hazards analysis using these markers as covariates at entry and as time-dependent covariates. The combination of the three markers was associated with development of AIDS in 6 of 7 men within 15 months. In contrast, the group that lacked any of these markers had a very low risk (11%) for developing AIDS. In groups with one or two of these three markers, progression rates were 33% and 66%, respectively. These data demonstrate that measurement of T cell function in vitro is of value for staging of HIV infection and may be useful for monitoring therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Predictors for non- and slow progression in human immunodeficiency virus (HIV) type 1 infection: low viral RNA copy numbers in serum and maintenance of high HIV-1 p24-specific but not V3-specific antibody levels.

To gain insight into determinants that define the duration of the asymptomatic period preceding AIDS, groups of long-term asymptomatic (LTA) person (> 7 years of follow-up) and slow and rapid progressors of human immunodeficiency virus infection were studied. LTAs had no clinical manifestations of AIDS or immunologic abnormalities in 7 years of follow-up. RNA copy numbers, gag- and env-specific, and neutralizing antibody titers in serum were determined 1 and 5 years after seroconversion or entry into the cohort. Early in infection, before immunologic markers or clinical manifestations allowed group discrimination, subjects who were later classified as LTAs had significantly less serum viral RNA than progressors. No significant increase in virus load was found in progressors, indicating that the initial load defines clinical outcome. In slow progressors, high virus load was associated with high p24-specific antibody titers, suggesting that delay of clinical manifestations of AIDS may be related to the presence of high levels of p24-specific but not V3-specific antibodies.

Acquired Immunodeficiency Syndrome↗
PubMed1995

The predictive value of T cell function in vitro and pre-AIDS zidovudine use for survival after AIDS diagnosis in a cohort of homosexual men in Amsterdam.

The best independent predictors of survival after AIDS diagnosis were determined in 160 homosexual men from the Amsterdam Cohort Study (1987 CDC case definition). In a Cox model, all pre-AIDS laboratory markers gathered during follow-up in the study did not independently predict survival after AIDS. A second analysis, using data available only at AIDS diagnosis, revealed that T cell reactivity after stimulation with phytohemagglutinin and monoclonal CD3 antibodies and the CD4+ cell count at diagnosis were independent predictors of survival. In an interval-based Cox model, the predictive value of pre-AIDS zidovudine use was determined. One year after AIDS diagnosis, participants with pre-AIDS zidovudine use had a worse survival probability (relative hazard = 3.99). In conclusion, the survival probability of homosexual men with AIDS can be estimate adequately using information obtained at clinical AIDS diagnosis. Analysis revealed the important predictive value of T cell function tests in vitro.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Lower prevalence and incidence of HIV-1 syncytium-inducing phenotype among injecting drug users compared with homosexual men.

OBJECTIVE: To study the prevalence, incidence and predictive value for progression to AIDS of the HIV-1 syncytium-inducing (SI) phenotype in HIV-infected injecting drug users (IDU) compared with HIV-infected homosexual men. DESIGN: Two prospective cohort studies on HIV-1 infection among IDU and homosexual men. METHODS: HIV-infected IDU (n = 225) and homosexual men (n = 366) without AIDS were studied from March 1989 through December 1993. Data on laboratory markers, including the presence of SI variants, demographics, behavioural characteristics and clinical events were collected at every visit. RESULTS: At baseline, SI variants were detected in 4% of IDU and 17% of homosexual men. During the study period 18 IDU and 68 homosexual men switched from non-SI to SI phenotype (4-year cumulative incidence, 14.6 and 28.4%, respectively) before AIDS diagnosis. Among participants with a documented date of HIV infection the cumulative incidence of SI was lower among IDU than homosexual men (4-year cumulative incidence, 6.2 and 20.7%, respectively). At AIDS diagnosis, 21% of all AIDS cases among IDU had the SI phenotype compared with 54% among homosexual men. In both risk groups an accelerated CD4 decline was found after the non-SI-to-SI switch. The SI phenotype appeared to be a predictor of AIDS (multivariate relative hazard, 5.33), independent of CD4 cell count and p24 antigen at baseline. In the multivariate time-dependent analysis, the relative hazard of SI phenotype decreased considerably, which is consistent with the hypothesis that the effect of SI phenotype on progression to AIDS is mediated by CD4 cell count. CONCLUSION: The SI phenotype is associated with accelerated CD4 decline and progression to AIDS in both risk groups. The remarkable lower prevalence and incidence of the SI phenotype among IDU may implicate a difference in pathogenesis and natural history of HIV infection linked to transmission group.

Adult↗
PubMed1995

Induction of a primary human cytotoxic T-lymphocyte response against a novel conserved epitope in a functional sequence of HIV-1 reverse transcriptase.

OBJECTIVE: To identify novel major histocompatibility complex (MHC) class I-restricted cytotoxic T-lymphocyte (CTL) epitopes conserved in HIV-1. METHODS: Potential conserved CTL epitopes were selected using a predictive computer algorithm based on a human leukocyte antigen (HLA)-A*0201 peptide-binding motif and tested for actual binding to the human processing defective cell line 174.CEM T2 (T2). Hence, the amino-acid sequences of 14 full-length sequenced HIV-1 strains were analysed. An in vitro primary peptide-specific human CTL response was induced with responding lymphocytes of an HIV-1-seronegative donor. Responding T cells were cloned by limiting dilution and tested for their ability to recognize naturally processed antigen in a 51Cr-release assay using recombinant vaccinia-HIV protein-infected B-lymphoblastoid cells (B-LCL) as target cells. RESULTS: The analysis of peptides bearing the HLA-A*0201 motif for conservation resulted in one peptide of Env, three of Gag and 12 of Pol. Only Gag340-348, Pol83-92, Pol267-277 and Pol960-968 showed binding properties to T2 comparable with those of known CTL epitopes Gag76-84 SLYNTVATL and Pol468-476 ILKEPVHGV. A successful primary MHC class I-restricted CTL response was induced against Pol468-476 and Pol267-277 VLDVGDAYFSV, a peptide in a functional sequence of reverse transcriptase (RT). The resulting CD8+ CTL clones were peptide-specific and able to specifically lyse recombinant vaccinia-HIV-1 RT-infected HLA-A*0201-matched B-LCL. CONCLUSION: The method used to screen proteins sequences for potential CTL epitopes, test selected peptides for binding to MHC class I and induction of an in vitro primary response against optimal binding peptides resulted in the identification of at least one novel conserved CTL epitope. The novel epitope is located in an area crucial for RT activity. This study demonstrates the feasibility of identifying highly conserved HIV-1-derived peptides capable of eliciting novel anti-HIV-1 CTL responses.

Amino Acid Sequence↗
PubMed1995

Immunologic and virologic markers determining progression to AIDS.

Infection with the human immunodeficiency virus type 1 (HIV-1) results in a severe immunodeficiency characterized by a depletion of CD4+ T-helper cells. Furthermore, it is well documented that in asymptomatic persons the number of CD4+ cells is also a good predictor of progression to AIDS. However, persons with similar CD4+ cell counts may differ with regard to clinical progression. For this reason the development of additional markers predictive of disease progression is of major clinical importance. In this review three additional progression markers are discussed: rate of decline of CD4+ cells, T-cell reactivity, and HIV biological phenotype. Besides their usefulness as independent progression markers they also provided insight into immunopathologic mechanisms responsible for the eventual development of AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Productive HIV-1 infection of macrophages restricted to the cell fraction with proliferative capacity.

Retroviruses establish productive infection only in proliferating cells. Macrophages are often considered to be non-proliferating in vitro yet are susceptible to HIV-1 infection. This has led to the conclusion that HIV-1 can establish infection independent of host cell proliferation. We here report that a small proportion of macrophages does have proliferative capacity. A comparable small fraction of monocyte derived macrophages (MDM) supported productive HIV-1 infection as demonstrated in limiting dilution culture. Fluorescence activated cell sorting on the basis of incorporation of BrdUrd, a thymidine analog, and subsequent PCR analysis revealed the presence of proviral DNA only in the BrdUrd positive cell fraction with DNA synthesizing activity. To identify which phase of cell cycle is required for establishment of productive infection, growth arrest in G1 or G1/S phase prior to inoculation was performed. gamma-Irradiation, which arrests primary cells in G1, prevented both cell proliferation and establishment of productive infection in MDM. Treatment of MDM with aphidicolin, a specific inhibitor of DNA polymerase alpha and delta which arrests cells in G1/S phase of the cell cycle, also inhibited DNA synthesis but did not prevent establishment of productive infection which is completely analogous to observations in T cells. Our data thus indicate that not cell division itself but cellular conditions that coincide with cell proliferation are apparently indispensable for establishment of productive infection.

Aphidicolin↗
PubMed1994

Changes in cytokine secretion patterns of CD4+ T-cell clones in human immunodeficiency virus infection.

In addition to the loss of CD4+ T cells in later stages of human immunodeficiency virus (HIV) infection, functional defects of Th cells can already be observed in early infection. Decreased interleukin (IL)-2 and interferon (IFN)-gamma production by CD4+ T cells and diminished delayed type hypersensitivity reactions are indicative for impaired Th1 responses. We studied the cytokine secretion patterns of T-cell clones (TCC) generated by mitogenic stimulation of CD4+ memory T cells. Compared with TCC from HIV-negative controls, TCC isolated from HIV-infected individuals consistently showed increased IL-4 production, often paralleled by increased IL-5 and decreased IFN-gamma production. This resulted in a decreased percentage of Th1 clones with an increase in Th0 clones. To rule out the influence of interindividual differences, we studied two individuals from whom cells were available before and after infection with HIV. Indeed, an increase in Th2 cytokine secretion was observed after HIV-infection. Loss of Th1 and enhanced Th2 responses might further curtail cellular responses resulting in deficiency of cellular immunity in HIV infection.

CD4-Positive T-Lymphocytes↗
PubMed1994

Simultaneous regulation of CD2 adhesion and signaling functions by a novel CD2 monoclonal antibody.

Accessory molecules on T cells can support adhesion and transduce agonistic signals that facilitate Ag receptor-induced T cell activation. The T cell differentiation Ag CD2 may exert both functions, as has been amply demonstrated in studies with CD2 mAbs. In addition, experiments in which either purified ligand (CD58) or transfected CD2 and CD58 molecules were used have confirmed this notion. However, controversy exists as to whether CD2 alters its affinity for CD58 in the course of T cell stimulation, and whether this putative affinity change affects CD2-mediated activation signals. We now describe a CD2 mAb (HIK27) that recognizes an epitope constitutively expressed on resting T cells and induces increased adhesiveness of CD2 toward CD58. Addition of HIK27 to a stimulatory but nonmitogenic pair of CD2 mAbs induces a strong proliferative response. Finally, HIK27 was found to be co-mitogenic with CD58 expressed on sheep erythrocytes, B cell lines, and CD58-transfected L cells. The simultaneous modulation of CD2 adhesion and signaling on HIK27 binding suggests that both functions of the molecule may be enhanced in the course of T cell stimulation.

Animals↗
PubMed1994

Glucosidase trimming inhibitors preferentially perturb T cell activation induced by CD2 mAb.

Glycosidase trimming inhibitors may be used to study contribution of N-linked glycan moieties in T cell function. We have studied the effects of castanospermine (Cas), swainsonine (Swain), 1-deoxynojirimycin (dNM), and 1-deoxymannojirimycin (dMM) on T cell activation and differentiation. Our analysis included a new dNM derivative, N-pentyl-1-deoxynojirimycin (pentyldNM). Previous reports showed inhibitory action of trimming inhibitors, such as Swain and Cas, on pokeweed mitogen-driven immunoglobulin (Ig) production. We extend these findings for pentyldNM and observed that glucosidase inhibitors, Cas and pentyldNM were effective in inhibiting CD2 and CD3 monoclonal antibody (mAb) driven Ig production. The pattern of inhibition by mannosidase and glucosidase inhibitors correlated with inhibitory action on T cell activation: only glucosidase trimming inhibitors (Cas and pentyldNM with comparable potency) perturbed mAb-induced T cell activation, in particular if induced by CD2 mAb. Expression of the early activation marker CD69 was not decreased in the presence of these inhibitors, while addition of exogenous recombinant interleukin-2 partially overcame inhibitory effects during proliferation. These findings suggest that glucosidase, but not mannosidase, trimming inhibitors interfere with a late phase of T cell activation. In addition, the enhanced sensitivity of CD2 mAb-induced proliferation for glucosidase trimming inhibitors suggests dependence on N-linked glycans during CD2-mediated adhesion and triggering functions.

1-Deoxynojirimycin↗
PubMed1994

Characteristics of long-term asymptomatic infection with human immunodeficiency virus type 1 in men with normal and low CD4+ cell counts.

From a cohort study of homosexual men in Amsterdam, 61 human immunodeficiency virus (HIV)-infected men who had remained asymptomatic for at least 7 years were identified. In a nested case control study, these men were compared with 142 men who progressed symptomatic HIV infection (CDC class IV) within 7 years, regarding laboratory markers, sexual behavior, psychologic coping, and drug use. Of the 61 long-term asymptomatic men, 13 had a CD4+ cell count > or = 500/mm3 after 7 years; in 2 of these 13, the CD4+ cell count had not declined during follow-up. Independent of CD4+ cell count, long-term asymptomatic HIV-1 infection was characterized by stable T cell reactivity after stimulation with monoclonal CD3 antibodies, seropositivity for antibodies to HIV core proteins, and the absence of hepatitis B markers. No association with markers of high-risk sex or the recreational use of drugs was found. Long-term asymptomatic men had a slightly lower score regarding the coping behavior active problem-solving; no other associations with coping behaviors were found.

Adult↗
PubMed1994

Associations between HLA frequencies and pathogenic features of human immunodeficiency virus type 1 infection in seroconverters from the Amsterdam cohort of homosexual men.

HLA-disease associations may be important for understanding the pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection. Therefore, 106 homosexual men from the Amsterdam Cohort Study on AIDS with a known date of HIV-1 seroconversion were serologically typed for HLA. Several significant associations between HLA type and pathogenic features of HIV-1 infection were observed: Subjects with fever and skin rash during primary HIV-1 infection showed an increased frequency of HLA-B62 (relative risk [RR], 5.8; P = .005). The frequency of HLA-B35 was increased in subjects with a rapid decline in CD4+ T lymphocytes (RR, 3.2; P = .021). Kaplan-Meier survival analysis revealed a significant association between HLA-B35 and a decrease in CD4+ cells to < 200/microL (P = .01). The strongest association was found between HLA-DR1 and AIDS-related Kaposi's sarcoma (RR, 22.5; P < .001), also confirmed in survival analysis (P = .001). In AIDS patients with only opportunistic infections, increased frequencies of HLA-DR3 (P = .011) and -DQ2 (P = .007) were observed. Finally, the occurrence of syncytium-inducing HIV-1 variants was significantly associated with HLA-DQ2 (P = .01).

Cohort Studies↗
PubMed1994

Viro-immunological studies in acute HIV-1 infection.

OBJECTIVE: To monitor a patient who presented with symptomatic HIV-1 infection for virological and immunological parameters in relation to the clinical course. METHODS: Virological studies included determination of frequency of productively HIV-1-infected peripheral blood mononuclear cells (PBMC) and viral RNA load in plasma and p24 antigenaemia. Immunological studies included the analysis of T-cell subsets, the expression of activation markers, CD45RO and CD45RA antigens, the frequency of cells programmed for death, and T-cell function. RESULTS: During the first week post onset of primary HIV-1 infection symptoms high plasma titres of p24 and HIV-1 RNA were observed. The number of productively HIV-1-infected PBMC peaked, coinciding with CD4+ T lymphocytopaenia, during week 2 when clinical improvement started. CD8+ T lymphocytosis was observed 10 days post onset of clinical symptoms, the expanded cell population being of the CD8+CD38+, CD8+CD27+ and CD8+CD28- phenotype. CD8+ T lymphocytosis was paralleled by a high percentage of cells undergoing programmed cell death on in vitro culture. In vitro T-cell function was severely depressed during the first 10 days post onset of clinical symptoms. Within about 3 weeks, following resolution of clinical symptoms, phytohaemagglutinin-induced proliferation was restored to normal levels while responses to the CD3 monoclonal antibody only showed a partial restoration. During follow-up, concomitant with the rise of activated CD8+ T cells, p24 antigen levels and viral RNA load in serum as well as the number of HIV-producing PBMC steeply declined after 2 weeks. CONCLUSION: These findings demonstrate HIV-1-induced abnormalities during severe clinical symptoms of primary HIV-1 infection. The subsequent strong immune response, which is believed to be responsible for efficient control of viral replication, appears to precede clinical improvement.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Predictors of disease progression in HIV-infected homosexual men with CD4+ cells < 200 x 10(6)/l but free of AIDS-defining clinical disease.

OBJECTIVE: To study progression of HIV infection in individuals who are free of AIDS-defining clinical disease with CD4+ cell counts < 200 x 10(6)/l. DESIGN: Prospective and nested case-control study. SETTING: Amsterdam cohort study on HIV infection, The Netherlands. PARTICIPANTS: Prospective study: 148 asymptomatic HIV-infected individuals with < 200 x 10(6)/l CD4+ cells. Nested case-control study: 58 men with AIDS-free follow-up more than 2 years after CD4 count < 200 x 10(6)/l, compared with 63 who progressed to AIDS within 2 years. MAIN OUTCOME MEASURES: Progression to AIDS according to the 1987 Centers for Disease Control and Prevention case definition and death. RESULTS: Median AIDS-free interval was 22 months, median interval to death 41 months. Presence of syncytium-inducing (SI) HIV variants, HIV p24 antigen, and a low T-cell response after stimulation with phytohaemagglutinin (PHA) were independent predictors of progression to AIDS. Probability of 1 year AIDS-free survival varied between 89 and 38% by the presence or absence of these additional markers. Effect of early treatment could only be detected in men with HIV p24 antigen and SI variants. Case-control analysis showed similar changes over time regarding prognostic markers in both groups although at a lower rate in the AIDS-free men. Eight men remained AIDS-free more than 4 years, SI variants were absent in seven, and all eight were p24-seronegative. CONCLUSIONS: HIV-infected individuals can remain disease-free for more than 4 years with very low CD4+ cell counts, provided that they lack other progression markers: SI variants, p24 antigen and a low PHA-induced T-cell reactivity. A beneficiary effect of early treatment may be limited to men with SI variants and/or p24 antigen.

Acquired Immunodeficiency Syndrome↗