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Biomedical subjects

F Miedema

Publications and source records attributed to F Miedema.

At least 55 records · Page 3Linked to original sources
PubMed1999

Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts.

To assess possible differences in immune status, proportions and absolute numbers of subsets of CD4+ and CD8+ T cells were compared between HIV- healthy Ethiopians (n = 52) and HIV- Dutch (n = 60). Both proportions and absolute numbers of naive CD4+ and CD8+ T cells were found to be significantly reduced in HIV Ethiopians compared with HIV- Dutch subjects. Also, both proportions and absolute numbers of the effector CD8+ T cell population as well as the CD4+CD45RA-CD27- and CD8+CD45RA-CD27- T cell populations were increased in Ethiopians. Finally, both proportions and absolute numbers of CD4+ and CD8+ T cells expressing CD28 were significantly reduced in Ethiopians versus Dutch. In addition, the possible association between the described subsets and HIV status was studied by comparing the above 52 HIV- individuals with 32 HIV+ Ethiopians with CD4 counts > 200/microliter and/or no AIDS-defining conditions and 39 HIV+ Ethiopians with CD4 counts < 200/microliter or with AIDS-defining conditions. There was a gradual increase of activated CD4+ and CD8+ T cells, a decrease of CD8+ T cells expressing CD28 and a decrease of effector CD8+ T cells when moving from HIV- to AIDS. Furthermore, a decrease of naive CD8+ T cells and an increase of memory CD8+ T cells in AIDS patients were observed. These results suggest a generally and persistently activated immune system in HIV- Ethiopians. The potential consequences of this are discussed, in relation to HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Functional T cell reconstitution and human immunodeficiency virus-1-specific cell-mediated immunity during highly active antiretroviral therapy.

Lymphoproliferative responses (LPRs) to recall antigens (Ags) and human immunodeficiency virus type 1 (HIV-1) Gag and frequencies of circulating HIV-1-specific cytotoxic T lymphocyte precursors (CTLps) were measured in 12 patients undergoing highly active antiretroviral therapy (HAART) after long-standing HIV-1 infection. LPRs to at least 1 recall Ag became detectable or increased in all patients during HAART. No significant LPRs to Gag-p24 were observed, whereas 4 of 8 patients tested presented with Gag-p17-specific LPRs. HIV-1-specific CTLp frequencies became measurable or increased early during therapy in 6 of 10 patients tested and were maintained or decreased thereafter. Increasing HIV-1-specific CTLp frequencies were seen only in association with partial HAART failure in 1 patient. In conclusion, restoration of CD4+ T lymphocyte responsiveness to recall Ags is achieved during HAART. The data provide evidence for limited HIV-1-specific CD4+ memory T cells during advanced HIV-1 infection and suggest that both CD4+ and CD8+ HIV-1-specific T cells are poorly stimulated when viral load is suppressed.

Adult↗
PubMed1999

Consistent associations of HLA class I and II and transporter gene products with progression of human immunodeficiency virus type 1 infection in homosexual men.

Polymorphic products of genes in the HLA region contributing to variability in the course of human immunodeficiency virus type 1 (HIV-1) infection were identified by screening 375 Caucasian seroconverters who were aggregated from 3 cohorts. AIDS-free time was related to numerous (15) class I alleles, alone or in conjunction with transporter protein variants, to homozygosity at the A or B locus, and to alleles of two class II haplotypes. A prognostic scoring algorithm derived from the 3 cohorts captured multiple HLA contributions to protection or to risk (relative hazard=0.57-60 per unit increase in score, all P<<.001). The impact of HLA was strong and appeared independent of the effects of chemokine receptor/ligand polymorphisms and antiretroviral treatment. The algorithm also predicted divergent rates of CD4+ cell decline in 2 other groups, totaling 227 seropositive persons (P=.06 - <.001). Confirmation of these relationships should encourage investigation of HIV-1 antigen processing and presentation mediated by polymorphisms in the HLA region.

Adult↗
PubMed1999

Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults.

Today's antiretroviral combination regimens can induce significant and sustained decreases in human immunodeficiency virus (HIV)-RNA levels, allowing the immune system to recover. To what extent immune reconstitution is possible and what factors determine the outcome have thus far not been resolved. We studied 19 subjects, treated for 2 years with protease inhibitor-containing triple therapy, who had a strong suppression of HIV-RNA levels. CD4+ T-cell numbers increased from medians of 170 to 420x106 cells/L, but in a number of subjects T-cell numbers did not further increase after week 72, without having reached normal values. Long-term CD4+ T-cell change was mainly caused by a slow but continuous increase in naive CD4+ T cells (CD45RA+CD62L+) and was predicted by the baseline number of these cells. Our data indicate that long-term immunological recovery is gradual, even during strong suppression of viral replication, not always complete, and dependent on the preexisting level of naive CD4+ T cells.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Treatment with granulocyte colony-stimulating factor decreases the capacity of hematopoietic progenitor cells for generation of lymphocytes in human immunodeficiency virus-infected persons.

An obstacle to stem cell gene therapy for AIDS is the limited numbers of hematopoietic progenitors available. Granulocyte colony-stimulating factor (G-CSF) is used for mobilization of progenitors, but little is known about the functional characteristics of mobilized progenitors, and immature and T cell progenitors may not be mobilized. This study examined the effect of G-CSF on the function of progenitors. Ten human immunodeficiency virus-infected patients received G-CSF (filgrastim, 300 microgram/day) for 5 days. Absolute numbers of immature and T cell progenitors did not increase. The ability of CD34+ progenitor cells to generate lymphocytes was examined by use of thymic organ cultures. The mean number of lymphocytes generated per CD34+ cell on day 0 was 0.72 and on day 4 was 0.09 (P<.003). The number of CD4+ cells generated per CD34+ cell was significantly reduced after G-CSF treatment. Thus, G-CSF increased the number of mature progenitor cells but did not increase T cell progenitors.

Animals↗
PubMed1999

Evidence that human CD8+CD45RA+CD27- cells are induced by antigen and evolve through extensive rounds of division.

We recently showed that circulating human CD8(+) effector cells have a CD45RA+CD27(-) membrane phenotype. In itself this phenotype appeared to pose a paradox: CD45RA, a marker expressed by unprimed cells, combined with absence of CD27, characteristic for chronically stimulated T cells. To investigate whether differentiation towards the CD45RA+CD27(-) phenotype is dependent on antigenic stimulation and involves cellular division, TCR Vbeta usage and telomeric restriction fragment (TRF) length were analyzed within distinct peripheral blood CD8(+) subsets. FACS analysis showed that the TCR Vbeta repertoire of CD8(+)CD45RA+CD27(-) cells differed significantly from that of unprimed CD8(+)CD45RA+CD27(+) cells. Moreover, in two out of six individuals large expansions of particular Vbeta families were observed in the CD8(+)CD45RA+CD27(-) subset. CDR3 spectrotyping and single-strand confirmation analysis revealed that within the CD8(+)CD45RA+CD27(-) population most of the 22 tested Vbeta families were dominated by oligoclonal expansions. The mean TRF length was found to be 2.3+/-1.0 kb shorter in the CD8(+)CD45RA+CD27(-) subset compared with the unprimed CD8(+)CD45RA+CD27(+) population, but did not differ substantially from that of memory type, CD8(+)CD45RA-CD27(+) T cells. These findings indicate that the CD8(+)CD45RA+CD27(-) cytotoxic effector population consists of antigen-induced, clonally expanded cells and confirm that the expression of CD45RA is not a strict marker of antigen non-experienced T cells.

CD8-Positive T-Lymphocytes↗
PubMed1999

Longitudinal phenotypic analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes: correlation with disease progression.

Few studies have examined longitudinal changes in human immunodeficiency virus type 1 (HIV)-specific cytotoxic T lymphocytes (CTL). To more closely define the natural history of HIV-specific CTL, we used HLA-peptide tetrameric complexes to study the longitudinal CD8(+) T-cell response evolution in 16 A*0201-positive untreated individuals followed clinically for up to 14 years. As early as 1 to 2 years after seroconversion, we found a significant association between high frequencies of A*0201-restricted p17(Gag/Pol) tetramer-binding cells and slower disease progression (P < 0.01). We observed that responses could remain stable over many months, but any longitudinal changes that occurred were typically accompanied by reciprocal changes in RNA viral load. Phenotypic analysis with markers CD45RO, CD45RA, and CD27 identified distinct subsets of antigen-specific cells and the preferential loss of CD27(+) CD45RO(+) cells during periods of rapid decline in the frequency of tetramer-binding cells. In addition we were unable to confirm previous studies showing a consistent selective loss of HIV-specific cells in the context of sustained Epstein-Barr virus-specific cell frequencies. Overall, these data support a role of HIV-specific CTL in the control of disease progression and suggest that the ultimate loss of such CTL may be preferentially from the CD27(+) CD45RO(+) subset.

Disease Progression↗
PubMed1998

Diversity of the T-cell receptor BV repertoire in HIV-1-infected patients reflects the biphasic CD4+ T-cell repopulation kinetics during highly active antiretroviral therapy.

OBJECTIVES: Highly active antiretroviral therapy (HAART) induces a decline in viral load and a biphasic increase in peripheral blood CD4+ T-cell counts in HIV-infected patients. To evaluate the effect of HAART on T-cell receptor (TCR) diversity of repopulating naive and memory CD4+ T cells, complementarity determining region 3 (CDR3) spectratyping was performed. DESIGN: For four patients treated with HAART, CD45RO+ (memory) and CD45RA+ (naive) CD4+ T cells were isolated from peripheral blood leukocyte samples obtained 1 week before, 1-2 months after, and 9-11 months after start of treatment. METHODS: CDR3 regions were amplified by TCR-BV-specific nested PCR from CD4+ T-cell subsets. CDR3 size distributions and single-strand conformation polymorphism profiles were compared as an indication for TCR diversity. RESULTS: Increasing blood CD4+ T-cell counts during the first 2 months of treatment coincided with increased perturbation of CDR3 patterns in CD4+ T-cell subsets, suggesting an early oligoclonal repopulation. At later timepoints, CDR3 size diversity increased when T-cell counts did not substantially decrease. Memory and naive CD4+ T cells generally showed comparable levels of perturbation. CONCLUSION: Diversity of the TCR repertoire reflected biphasic T-cell repopulation during HAART, compatible with initial redistribution and later CD4+ T-cell production. Sustained elevation of T-cell counts will in principle result in restoration of TCR diversity.

Anti-HIV Agents↗
PubMed1998

Restored humoral immune response to influenza vaccination in HIV-infected adults treated with highly active antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) effectively suppresses replication of HIV and is accompanied by an increase in CD4+ T lymphocytes. Whether the increase in CD4+ T lymphocytes in the blood is a reflection of a reconstitution of the immune functions is unknown. We investigated the recovery of the humoral immune response during HAART after immunization with T-cell-dependent influenza vaccine. METHODS: Forty-one men and three women infected with HIV and treated with HAART, and 15 healthy hospital staff members were immunized with trivalent influenza subunit vaccine. Antibody titres were determined by haemagglutination inhibiting assay in sera obtained before and 30 days after immunization. Lymphocyte subsets were determined in blood samples taken at the time of vaccination. RESULTS: In all HIV-infected individuals, treatment with HAART caused a median reduction of 2.3 log10 in HIV-1 load. The median increase of CD4+ T lymphocytes after initiation of HAART was 170 x 10(6)/l. The antibody response to influenza antigens was proportional to the number of memory CD4+ T lymphocytes in the blood at the time of vaccination. When a group of patients and healthy controls with approximately similar CD4+ T-lymphocyte counts were considered, the antibody titres after vaccination for influenza strain H1N1 and influenza B did not differ between patients and controls (P=0.12). Vaccination of patients with a CD4+ T-lymphocyte count of < 200 x 10(6)/l (mean 85 x 10(6)/l) before the start of HAART and with a mean of 282 x 10(6)/l CD4+ T lymphocytes at the time of vaccination as a result of HAART, demonstrated a substantial antibody response whereas patients with a CD4+ T lymphocyte count of < 200 x 10(6)/l (mean 56 x 10(6)/l) not treated with HAART (historical controls), and vaccinated with a similar influenza vaccine, failed to induce an antibody response. CONCLUSION: The present findings demonstrate a recovery of the humoral immune response to influenza antigens in HIV-infected individuals treated with HAART. This indicates that functional improvement of antigen specific CD4+ T helper cell reponses occurs.

Adult↗
PubMed1998

Low T-cell responses to CD3 plus CD28 monoclonal antibodies are predictive of development of AIDS.

OBJECTIVE: Decreased T-cell reactivity in vitro is strongly associated with progression to AIDS and low CD4+ T-cell numbers. Low T-cell responses in vitro induced by CD3 monoclonal antibody (mAb) are predictive for progression to AIDS independent of low CD4+ T-cell counts and high HIV-1 RNA levels. We developed a whole-blood lymphocyte culture system in which T cells were stimulated by a combination of CD3 and CD28 mAb. Combined stimulation of CD28, a costimulatory molecule, and CD3 considerably enhances T-cell responses in vitro and reduces variation coefficients, which may increase the prognostic power of T-cell responses. DESIGN: A prospective study of HIV-1-infected homosexual men followed for 35 months. METHODS: The predictive value of low T-cell responses to CD3 plus CD28 mAb relative to low CD4+ T-cell counts, high HIV-1 RNA levels and the presence of syncytium-inducing (SI) HIV-1 variants was evaluated longitudinally in 202 HIV-1-infected homosexual men followed for 35 months. RESULTS: In multivariate analysis, decreased T-cell responses at baseline were predictive of development of AIDS, independent of low CD4+ T-cell numbers and high HIV-1 RNA levels. In a time-dependent model, HIV-1 RNA levels lost their predictive value, whereas low T-cell responses, low CD4+ T-cell numbers and the presence of SI HIV-1 variants independently predicted AIDS. CONCLUSIONS: These data demonstrate that combined use of virological and immunological markers may be useful in monitoring disease progression and response to antiretroviral therapy.

Antibodies, Monoclonal↗
PubMed1998

Telomeres and HIV-1 infection: in search of exhaustion.

Telomere length analysis could be helpful in determining if exhaustion and replicative senescence are involved in HIV-1 pathogenesis. Evidence that CD8+ T cells have shorter telomeres may point towards an increased turnover of CD8+ T cells and exhaustion of the CD8+ T-cell responses in HIV-1 infection. In CD4+ T cells, the relationship between telomere length and turnover remains controversial; however, telomere length analysis argues against exhaustion of CD4+ T cells.

Biomarkers↗
PubMed1998

Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation.

The origin of CD4+ T cells reappearing in the blood following antiretroviral therapy in human immunodeficiency virus type-1 (HIV-1) infection is still controversial. Here we show, using mathematical modeling, that redistribution of T cells to the blood can explain the striking correlation between the initial CD4+ and CD8+ memory T-cell repopulation and the observation that 3 weeks after the start of treatment memory CD4+ T-cell numbers reach a plateau. The increase in CD4+ T cells following therapy most likely is a composite of initial redistribution, accompanied by a continuous slow repopulation with newly produced naive T cells.

Anti-HIV Agents↗
PubMed1998

Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy.

We show that the fraction of proliferating CD4+ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4+ T cells associated with the restoration of CD4+ T-cell counts. These results provide strong support for the idea of limited CD4+ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4+ T-cell production are still functional in early HIV infection.

Adult↗
PubMed1998

In vivo delayed-type hypersensitivity skin test anergy in human immunodeficiency virus type 1 infection is associated with T cell nonresponsiveness in vitro.

In a cross-sectional study, the prevalence of delayed-type hypersensitivity skin test anergy (DTHA) was examined in 136 asymptomatic human immunodeficiency virus-infected participants in relation to immunologic and virologic parameters. DTHA was assessed with a multitest cell-mediated immunity skin test. Of the 136 participants, with a mean CD4 T cell count of 335 x 10(6)/L, 25 were anergic (18.4%). In the stepwise forward multivariate logistic regression models, after adjustment for CD4 T cell counts, depending on whether it was analyzed continuously or after dichotomization (20th percentile), both T cell reactivity to CD2 plus CD28 antibodies or to CD3 antibodies were the most predictive markers of DTHA (odds ratio, 0.80; 95% confidence interval, 0.67-0.94; and odds ratio, 2.97; 95% confidence interval, 1.1-8.3, respectively). This study shows a strong correlation between the decreased T cell responses in vitro and DTHA. Therefore, next to DTHA testing, T cell function assays may be useful to test immune reconstitution observed during antiretroviral treatment.

Adult↗
PubMed1998

Longitudinal analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte responses: a predominant gag-specific response is associated with nonprogressive infection.

To establish correlates of protective immunity during human immunodeficiency virus type 1 (HIV-1) infection, the frequencies of circulating cytotoxic T lymphocyte (CTL) precursors (p) directed against 4 HIV-1 gene products (reverse transcriptase, gag, nef, and env) were evaluated in HIV-1-infected homosexual men who progressed to AIDS and in long-term survivors over time. For both groups, HIV-1-specific CTL responses had similar kinetics and magnitude. At maximum expansion, HIV-1-specific CTLp had a median frequency of 0.2% mononuclear cells in both progressors and long-term survivors, with peaks of 0.5% and 2%, respectively. Long-term survivors maintained the established CTLp pool and presented a persistently predominant gag-specific response. The fraction and, to a lesser extent, the frequency of gag-specific CTLp were inversely correlated with virus load. In progressors, general T cell function and measurable HIV-1-specific CTLp frequencies dropped simultaneously, suggesting a further loss of virus control due to the ensuing immunodeficiency.

Acquired Immunodeficiency Syndrome↗