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Biomedical subjects

F Miedema

Publications and source records attributed to F Miedema.

At least 73 records · Page 4Linked to original sources
PubMed1998

Characterization of HLA-B57-restricted human immunodeficiency virus type 1 Gag- and RT-specific cytotoxic T lymphocyte responses.

HLA-B57 has been shown to be strongly associated with slow disease progression in human immunodeficiency virus type 1 (HIV-1)-infected patients from the Amsterdam Cohort. Since HIV-1-specific CTL can control and eliminate virus-infected cells, we sought to characterize the dominant HLA-B57-restricted CTL responses at the epitope level. It was found that HLA-B57-restricted CTL responses were targeted at multiple proteins of HIV-1, with CTL specific for Gag and RT being the most pronounced. Gag-specific CTL recognized peptides ISPRTLNAW (aa 147-155) and STLQEQIGW (aa 241-249), which had previously been reported as HLA-B57-restricted. The RT-specific CTL response in one long-term survivor studied in great detail persisted for > 10 years and was dominated by HLA-B57-restricted CTL that recognized the newly defined epitope IVLPEKDSW (RT(LAI), aa 244-252). This epitope could be recognized in the context of both HLA-B*5701 and HLA-B*5801. Interestingly, three epitope variants of IVLPEKDSW were observed, which coincided with the strongest detectable CTL response to RT. One variant (T2E7) was not recognized by IVLPEKDSW-specific CTL despite the fact that this variant bound to HLA-B*5701 with a similar affinity as the index peptide. Finally, only viruses which contained the epitope index sequence were obtained suggesting efficient virus control by CTL. In conclusion, we report the characterization of dominant HIV-1 Gag- and RT-derived, HLA-B57-restricted CTL epitopes which are associated with longer time to AIDS. Further characterization of CTL responses restricted by HLA-B57 and other protective HLA alleles may contribute to the development of effective AIDS vaccines.

Alleles↗
PubMed1997

Patterns of T-cell repopulation, virus load reduction, and restoration of T-cell function in HIV-infected persons during therapy with different antiretroviral agents.

The effect of antiretroviral therapy on both T-cell numbers and T-cell function in peripheral blood was studied. CD4+ and CD8+ T-cell numbers, T-cell reactivity to CD3 monoclonal antibodies (mAb), and viral RNA load date were obtained from patients treated for at least 28 weeks with either the HIV-1 protease inhibitor ritonavir, the nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor nevirapine, or the nucleoside-analogue RT inhibitor zidovudine. Compared with both RT inhibitors, treatment with the protease inhibitor ritonavir resulted in the most significant and persistent elevation of CD4+ and CD8+ T-cell counts. However, in vitro T-cell functional improvement was of limited duration in the ritonavir-treated group and was inversely correlated with viral RNA load changes during the entire follow-up period. Thus, despite what can be assumed of responses during RT inhibitor therapy, quantitative responses on therapy did not necessarily correlate with qualitative immunologic responses, as can be seen during treatment with ritonavir. For optimal immune reconstitution, both numeric and functional immunologic improvements are essential. During antiretroviral therapy, measurement of in vitro improvement in immune function will be useful as a correlate for transient drug-induced alteration of immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Association between CCR5 genotype and the clinical course of HIV-1 infection.

BACKGROUND: Heterozygosity for a 32-nucleotide deletion in the C-C chemokine receptor 5 gene (CCR5 delta 32) is associated with delayed disease progression in persons infected with HIV-1. OBJECTIVE: To compare the predictive value of CCR5 genotype with that of established markers in the clinical course of HIV-1 infection. DESIGN: Retrospective longitudinal study and nested case-control study. The latter included only long-term survivors, who were individually matched with progressors. SETTING: Amsterdam, the Netherlands. PARTICIPANTS: 364 homosexual men with HIV-1 infection. MEASUREMENTS: Polymerase chain reaction was used for CCR5 genotyping. Univariate and multivariate Cox proportional hazard analyses were done for disease progression with CCR5 genotype, CD4+ T-lymphocyte counts, T-lymphocyte function, HIV-1 biological phenotype (syncytium-inducing or non-syncytium-inducing HIV-1), and viral RNA load in serum as covariates. RESULTS: In the case-control study, 48% of long-term survivors were heterozygous for CCR5 delta 32 compared with 9% of progressors (odds ratio, 6.9 [95% CI, 1.9 to 24.8]). In the total study sample, CCR5 delta 32 heterozygotes had significantly delayed disease progression (P < 0.001; relative hazard, 0.4 [CI, 0.3 to 0.6]), a 1.5-fold slower decrease in CD4+ T-lymphocyte count (P = 0.01), and a 2.6-fold lower viral RNA load (P = 0.01) at approximately 2.3 years after seroconversion compared with CCR5 wild-type homozygotes. At the end of the study, both groups showed the same prevalence of syncytium-inducing HIV-1, but CCR5 delta 32 heterozygotes had a delayed conversion rate. The protective effect of CCR5 delta 32 heterozygosity was stronger in the presence of only non-syncytium-inducing HIV-1. The CCR5 genotype predicted disease progression independent of viral RNA load, CD4+ T-lymphocyte counts, T-lymphocyte function, and HIV-1 biological phenotype. CONCLUSIONS: The addition of CCR5 genotype to currently available laboratory markers may allow better estimation of the clinical course of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

HIV-1 reverse transcriptase-specific CTL against conserved epitopes do not protect against progression to AIDS.

A small group of HIV-1-infected subjects who either do not progress to AIDS or progress only slowly have sustained HIV-1-specific CTL responses. It has been suggested that the specificities of these responses differ from the CTL responses of rapid progressors due to recognition of epitopes that are under structural or functional constraints. We have, in this respect, studied the CTL response to reverse transcriptase (RT) in long term survivors (LTS) and in HIV-1-infected individuals who progressed to AIDS within 3 to 6 yr. Both LTS and progressors displayed vigorous RT-specific CTL responses of comparable magnitude during the asymptomatic phase. From each individual at least two CTL lines were obtained from blood samples drawn at different time points during follow-up. A total of 19 CTL lines recognized nine different RT-derived epitopes. CTL obtained from progressors recognized epitopes with a similar degree of amino acid conservation as epitopes targeted by CTL from LTS. Furthermore, five of seven epitopes were recognized by both LTS and progressors. Moreover, one of the epitopes recognized by progressors contained the highly conserved YMDD motif that is essential for RT activity. In conclusion, our data imply that neither the magnitude nor the specificity of HIV-1-specific CTL against RT is a major cause of a more protracted course of disease.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Functional B cell abnormalities in HIV type 1 infection: role of CD40L and CD70.

Early in HIV-1 infection, B cell responses to T cell-dependent antigens are impaired. In addition to the receptor-ligand pair CD40/CD40L, CD27/CD70 also appears to be involved in T cell-dependent B cell stimulation. We have shown that CD70+ B cells are the main producers of Ig when stimulated in a T cell-dependent manner, and that CD70 upregulation is dependent on interaction of CD40L on T cells with CD40 on B cells. We confirm here that B cells from HIV-infected individuals are impaired in T cell-dependent Ig production in vitro. This dysfunction could partly be restored by adding allogeneic T cells to the culture. In contrast, IgG production induced by CD40 MAb, IgM MAb, and IL-10 was in the normal range. In line with this, CD70 upregulation on B cells from HIV-infected individuals was impaired after stimulation in vitro by activated T cells but not after stimulation with CD40 MAb and IgM MAb. Furthermore, CD40L expression was decreased on CD4+ T cells after stimulation in vitro. Finally, CD70 expression on freshly isolated B cells from HIV-infected individuals was decreased, and low CD70 expression correlated with low IgG production after T cell-dependent stimulation. In conclusion, our data strongly suggest that impaired B cell responses to T cell-dependent Ag in HIV-1 infection are due to a defect in T cells.

Antigens, CD↗
PubMed1997

Kinetics of immune functions and virus replication during HIV-1 infection.

INTRODUCTION: Kinetics of human immunodeficiency virus type 1 (HIV-1) cytotoxic T lymphocyte (CTL) responses and viral load were evaluated in HIV-1 infected homosexual men who progressed to AIDS within 3-6 years after seroconversion and in long-term survivors who remained AIDS-free for > 9 years with normal CD4+ T cell counts. METHODS: CTL against four major HIV-1 gene products (i.e. Gag, reverse transcriptase (RT), Nef and Env) were expanded in vitro under limiting dilution conditions using antigen specific stimulation. CTL activity was measured in standard split-well 51Cr-release assay. Viral load was measured both as serum HIV-1 RNA levels and frequency of circulating CD4+ T cells productively infected with HIV-1. Polyclonal T cell function in vitro was determined in whole blood lymphocyte cultures, measuring lymphoproliferative responses to CD3 monoclonal antibody. RESULTS: Long-term survival was associated with either persistently high or stable low HIV-1 specific CTL responses, accompanied by preserved in vitro polyclonal T cell reactivity and low viral load. In progressors, HIV-1 specific CTL responses were initially generated with similar kinetics as compared to long-term survivors. However, with progression to AIDS antiviral CTL activity and T cell function deteriorated simultaneously, while viral load increased. CONCLUSIONS: Our results are consistent with the hypothesis that HIV-1 specific CTL are beneficial through control of viremia to the virologic set-point and contribute to maintenance of the asymptomatic phase. However, loss of HIV-1 specific immune control as part of a more general loss of T cell function is the precipitating event in AIDS pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Analysis of CD8+ T lymphocyte-mediated nonlytic suppression of autologous and heterologous primary human immunodeficiency virus type 1 isolates.

Nonlytic CD8+ T lymphocyte antiviral factor (CAF) activity has been described as having an important role in the clinical course of human immunodeficiency virus type 1 (HIV-1) infection. Testing of CAF activity against autologous viruses isolated at approximately the same time points showed that CD8+ T lymphocytes from long-term survivors indeed possessed high CAF activity. However, in four of six progressors to AIDS, we observed the same amount of CAF activity in the face of increasing cellular HIV-1 load. In the other two progressors, CAF activity seemed preserved over time whereas the susceptibility of the virus isolate obtained late in infection seemed to be diminished. In a heterologous system, CAF activity of CD8+ T lymphocytes from 13 HIV-1-positive individuals did not correlate with CD4+ T lymphocyte counts. In two of three patients, syncytium-inducing (SI) HIV-1 variants, which are associated with a progressive clinical course, appeared to have a somewhat reduced susceptibility to CAF activity as compared to their coexisting non-SI HIV-1 variants. In a large donor group, suppression of SI isolates (as compared to non-SI isolates) mediated by heterologous CD8+ T lymphocytes was reduced. CD8+ T lymphocytes from five of six HIV-1-positive individuals suppressed HIV-1 replication in macrophages. CD8+ T lymphocytes from noninfected donors, even from cord blood, already had high CAF activity, suggesting that induction of this activity is neither virus nor HIV-1 specific.

Anti-HIV Agents↗
PubMed1997

Epstein-Barr virus-specific cytotoxic T cell responses in HIV-1 infection: different kinetics in patients progressing to opportunistic infection or non-Hodgkin's lymphoma.

Although the high incidence of EBV-associated diffuse large cell lymphomas (DLCL) in HIV-1 infection is believed to be related to loss of immune control due to HIV-induced immune deficiency, it has been claimed that cytotoxic T lymphocyte (CTL) responses to EBV are longer lasting in HIV-1-infected persons than CTL directed against HIV-1 itself. We approached this apparent paradox by performing the first longitudinal study into the kinetics of EBV and HIV-specific CTL responses in HIV-infected patients progressing either to AIDS with non-Hodgkin's lymphoma (NHL) or AIDS with opportunistic infection (OI). Multiple samples were tested from HIV-1 seroconversion to AIDS-diagnosis. Four out of six patients that were either long-term asymptomatic or progressing to OI showed declining HIV-1 CTL precursor (CTLp) frequencies whereas EBV-CTLp remained stable, suggestive for HIV-1-specific immune exhaustion. In two patients rapidly progressing to AIDS-OI, a parallel decline of HIV-1- and EBV-CTL responses was seen, indicative for total collapse of cellular immunity. In all these six patients EBV-load remained low. However, in four out of five patients that progressed to DLCL, EBV-load was high and increasing several months preceding the NHL. In all five patients, EBV-CTLp decreased before the emergence of the NHL. Thus, our data show that in HIV-1 infection loss of HIV-1-specific T cell immunity is not necessarily paralleled by loss of EBV-specific T cell responses. The occurrence of AIDS-related DLCL is preceded by decreasing EBV-CTLp and increasing EBV load. Failing EBV-control might therefore be an important step in the pathogenesis of AIDS-related DLCL.

AIDS-Related Opportunistic Infections↗
PubMed1997

Gag-specific immune responses after immunization with p17/p24:Ty virus-like particles in HIV type 1-seropositive individuals.

Gag-specific immune responses and changes in HIV-1 RNA levels were evaluated in eight HIV-1-infected persons, in order to assess the immunotherapeutic potential HIV-1 p17/p24: Ty virus-like particles (p24-VLP). All treated subjects showed transient and dose-dependent proliferative responses to the Ty-VLP carrier (stimulation index [SI], 2.0-119.5). Three of four individuals who received either 500 or 1,000 micrograms of p24-VLP also showed proliferative responses to p17 or p24 (SI, 2.0-15.7). In 2 subjects who were treated with either 500 or 1,000 micrograms of p24-VLP, enhanced Gag-specific CTL precursor (CTLp) frequencies were observed after immunization (10- to 14-fold). Both subjects had low baseline Gag-specific CTL activity (< 25 cTLp/10(6) PBMCs). In the other participants studied no significant boosting of preexisting Gag-specific CTL responses was observed. Short-term elevation of HIV-1 RNA levels at weeks 2 and 4 was observed in two subjects treated with the highest dose of p24-VLP. However, HIV-1 RNA levels at week 24 did not significantly differ from those found in the placebo group. In conclusion, p24-VLP induced marginal Gag-specific immune responses in limited numbers of HIV-1-seropositive individuals, with some showing transient elevation of HIV-1 viral load. Further studies are needed to establish potential clinical effects of these observations.

AIDS Vaccines↗
PubMed1997

Interleukin-12 (IL-12) production in whole blood cultures from human immunodeficiency virus-infected individuals studied in relation to IL-10 and prostaglandin E2 production.

The role of interleukin-12 (IL-12) in Th1 cell differentiation is well established. The heterodimer p70, composed of a p40 and a p35 chain, is the biologically active form. IL-12 production by human monocytes is enhanced by interferon-gamma (IFN-gamma) and inhibited by IL-10 and prostaglandin E2 (PGE2). Peripheral blood mononuclear cells from human immunodeficiency virus (HIV)-infected individuals reportedly have impaired IL-12 p40 and p70 production on stimulation with Staphylococcus aureus Cowan I (SAC) in vitro. Both PGE2 and IL-10 previously were proposed to be instrumental in this defect in IL-12 production. Here, we studied IL-12 p40 and p70 production in relation to IL-10 and PGE2 production in whole blood cultures from HIV-infected individuals. On stimulation with lipopolysaccharide, IL-12 production was normal. However, on stimulation with SAC, IL-12 p40 and p70 production was decreased in HIV-infected individuals and correlated significantly with decreased peripheral blood CD4+ T-cell number and T-cell reactivity to CD3 monoclonal antibody in vitro. However, IL-10 and PGE2 production in cultures from HIV-infected individuals was normal and did not relate to IL-12 production. In conclusion, IL-12 production by cells from HIV-infected individuals is impaired under certain conditions in vitro and this decrease is independent of IL-10 or PGE2 production.

Blood Cells↗
PubMed1997

Longitudinal analysis of CD4 T cell counts, T cell reactivity, and human immunodeficiency virus type 1 RNA levels in persons remaining AIDS-free despite CD4 cell counts <200 for >5 years.

CD4 cell count, T cell reactivity, and human immunodeficiency virus type 1 (HIV-1) RNA load were examined in 10 persons remaining free of AIDS while CD4 cell counts were <200/mm3 for >5 years, so-called low CD4 cell count long-term survivors (low CD4 LTS), and 10 matched rapid and 10 matched intermediate progressors (AIDS within 1 and 1-3 years). Longitudinal analysis of CD4 cell count and T cell reactivity revealed slower declines in low CD4 LTS. HIV-1 RNA load was 1 log/mL lower in the low CD4 LTS compared with the rapid progressors, with a similar linear increase over time in low CD4 LTS and progressors of 0.1 log/year. There was considerable overlap between groups. The constant difference between low CD4 LTS and progressors probably reflects HIV RNA load early after infection, but low CD4 LTS and progressors show similar slopes of HIV-1 RNA load rise.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Rapid disease progression in human immunodeficiency virus type 1-infected individuals with adverse reactions to trimethoprim-sulfamethoxazole prophylaxis.

We studied the relation between the occurrence of adverse reactions to trimethoprim-sulfamethoxazole (TMP-SMZ) prophylaxis and the subsequent course of human immunodeficiency virus (HIV) infection in a cohort of homosexual men. Adverse reactions to TMP-SMZ were associated with a more rapid progression to AIDS (P < .001) and death (P < .001) and with a more rapid decline in CD4+ cell counts (P = .001). The median time to progression to AIDS was 14.9 months in subjects with adverse reactions to TMP-SMZ and 32.5 months in those without adverse reactions. After exclusion of Pneumocystis carinii pneumonia (PCP) and toxoplasmosis from the case definition of AIDS, the differences in the rate of progression to AIDS between subjects with and without adverse reactions to TMP-SMZ were still highly significant (P = .004). A low CD4+ cell count at baseline and the use of antiretroviral agents before the start of prophylaxis were predictors of adverse reactions to TMP-SMZ but did not account for the difference in progression to AIDS between subjects with and without adverse reactions to TMP-SMZ. In a univariate analysis, the relative hazard of adverse reactions to TMP-SMZ for progression to AIDS was 2.54 (95% confidence interval [CI], 1.50-4.28); in a multivariate analysis, it was 2.21 (95% CI, 1.29-3.81). The relative hazards of adverse reactions to TMP-SMZ for progression to AIDS with the exclusion of PCP and toxoplasmosis, CD4+ cell counts of <50/mm3, and death were 2.16 (95% CI, 1.25-3.72), 2.37 (95% CI, 1.36-4.12), and 3.21 (95% CI, 1.80-5.72), respectively. It is unclear whether adverse reactions to TMP-SMZ induce or merely predict progression of HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed1997

Polymorphisms within the human tumor necrosis factor-alpha promoter region in human immunodeficiency virus type 1-seropositive persons.

The question is addressed whether particular tumor necrosis factor-alpha (TNF-alpha) polymorphisms are associated with clinical course and outcome of human immunodeficiency virus type 1 (HIV-1) infection. The distribution of four TNF-alpha guanine (G) to adenosine (A) transition polymorphisms at positions -376, -308, -238, and -163 of the 5' promoter region of the TNF-alpha gene was studied in a nested case-control study among HIV-1-seropositive participants of the Amsterdam Cohort. None of the polymorphisms was significantly associated with long-term asymptomatic survival after HIV-1 infection compared with progression to clinical AIDS. Moreover, specific AIDS-defining illnesses or biologic phenotype of the HIV-1 virus were not associated with TNF-alpha alleles. The results of this study do not point toward a role for known TNF-alpha G to A transition polymorphisms in the clinical course of HIV-1 infection.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Early and late HIV-1 RNA level and its association with other markers and disease progression in long-term AIDS-free homosexual men.

OBJECTIVE: To study the association between virological markers and clinical progression in individuals with long-term AIDS-free HIV infection. DESIGN: Seventy-seven HIV-infected participants in the Amsterdam cohort study who remained AIDS-free for at least 8 years were prospectively followed during that time and during a subsequent period in which 15 developed AIDS. METHODS: Serum HIV-1 RNA levels were evaluated at 1 and 8 years after study entry. Progression to AIDS following the 8 AIDS-free years was studied using Kaplan-Meier estimates and Cox proportional hazard analysis. RESULTS: HIV-1 RNA increased over time in a large proportion of these long-term AIDS-free men. Most subjects showed progressive immune system damage and/or clinical manifestations of HIV disease at year 8. High RNA levels at year 8 were significantly associated with symptomatic HIV Infection, low CD4+ T-cell count, p24 antigenaemia, low T-cell reactivity at year 8 as well as rapid annual CD4+ T-cell decline. High RNA level at year 1 was associated with high RNA levels at year 8 and low CD4+ T-cell count at year 1. In univariate analysis, RNA was associated with progression to AIDS after 8 years. In multivariate analysis, only the CD4+ T-cell count at year 8 remained significantly associated with progression to AIDS. CONCLUSIONS: In later stages of HIV infection, measures of immune deficiency may be more powerful prognostic markers than serum HIV-1 RNA level, indicating that optimal staging of the HIV-infected patient requires the combined use of RNA levels, CD4+ T-cell counts, and T-cell reactivity instead of RNA levels alone.

Acquired Immunodeficiency Syndrome↗
PubMed1997

AIDS prognosis based on HIV-1 RNA, CD4+ T-cell count and function: markers with reciprocal predictive value over time after seroconversion.

OBJECTIVE: HIV-1 RNA levels in peripheral blood are strongly associated with progression to AIDS, CD4+ T-cell decline, or death. Their predictive value is reportedly independent of the predictive value of CD4+ T-cell counts. Because the interrelations between these parameters of HIV-1 infection are poorly understood, we studied the kinetics and predictive value of serum HIV-1 RNA levels, CD4+ T-cell counts, and T-cell function. DESIGN AND METHODS: HIV RNA levels, CD4+ T-cell counts, and T-cell function were measured from seroconversion to AIDS in 123 homosexual men who seroconverted during a prospective study and were followed over 10 years. RESULTS: Two patterns of median HIV-1 RNA levels were found during infection: a steady-state and a 'U-shaped' curve. Steady-state high RNA levels were related to rapid disease progression. For the U-shaped curve, there were groups with high and low RNA levels related to disease progression. At 1 year after seroconversion, RNA level was the only marker that was strongly predictive. Furthermore, decreasing RNA levels in the first year following seroconversion were related to better prognosis than stable low levels. Low CD4+ T-cell count and T-cell function became predictive of progression to AIDS at 2 and 5 years after seroconversion, respectively. CONCLUSIONS: With ongoing infection, the predictive value of low CD4+ T-cell count and T-cell function increases, whereas the predictive value of high HIV-1 RNA level decreases. These findings reflect the observation that infection with HIV progressively leads towards immune deficiency, which in later stages is most predictive of disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Human immunodeficiency virus type 1 Rev- and Tat-specific cytotoxic T lymphocyte frequencies inversely correlate with rapid progression to AIDS.

Immunological correlates of AIDS-free survival after human immunodeficiency virus type 1 (HIV-1) infection are largely unknown. Cytotoxic T lymphocyte (CTL) responses are generally believed to be a major component of protective immunity against viral infections. However, the relationship between HIV-1-specific CTL responses and disease progression rate is presently unclear. Here we show in twelve HIV-1-infected individuals that detection of Rev-specific CTL precursors (CTLp) early in the asymptomatic stage, as well as detection of Rev- and Tat-specific CTLp later during follow-up, inversely correlate with rapid disease progression. No such correlation was found for detection of CTLp against Gag, RT or Nef. Further studies are required to determine whether a protective mechanism is indeed the basis of the observed correlation. The data presented are in agreement with the hypothesis that CTL against proteins that are important for early viral transcription and translation are of particular importance in protection from rapid disease progression.

Acquired Immunodeficiency Syndrome↗