Biomedical subjects

F de Wolf

Publications and source records attributed to F de Wolf.

At least 55 records · Page 3Linked to original sources

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

In vitro replication kinetics of human immunodeficiency virus type 1 (HIV-1) variants in relation to virus load in long-term survivors of HIV-1 infection.

In 7 long-term survivors (LTS) and 8 progressors, all carrying solely non-syncytium-inducing variants, a possible correlation between in vitro virus replicative capacity, virus load, and clinical course of human immunodeficiency virus type 1 (HIV-1) infection was analyzed. Late in infection, 3 LTS and 7 progressors had a high virus load, which coincided with the presence of rapid-replicating viruses. In contrast to progressors, LTS maintained relatively high and stable CD4 T cell counts. Four LTS persistently had relatively slow-replicating viruses and a low virus load, even after 6.6-9 years of seropositive follow-up. All virus isolates from 1 of these LTS had a 4-aa deletion in nef. These results suggest a correlation between the in vitro replicative capacity of non-syncytium-inducing HIV-1 variants and virus load. The presence of HIV-1 variants with relatively low replicative capacity throughout infection may have contributed to the beneficial clinical course in half of the LTS in this study.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Emergence of syncytium-inducing human immunodeficiency virus type 1 variants coincides with a transient increase in viral RNA level and is an independent predictor for progression to AIDS.

To study the dynamics of human immunodeficiency virus (HIV)-1 RNA level around the time of conversion from non-syncytium-inducing (NSI) to syncytium-inducing (SI) phenotype and to study the predictive value of the SI phenotype for progression to AIDS, sequential samples from 123 HIV-infected homosexual men with documented intervals of seroconversion were evaluated. The NSI-to-SI phenotype conversion coincided with a 3-fold increase in median RNA level, which was not observed in matched controls in whom a viral phenotype conversion did not occur. This increase in virus was followed by a decrease to a higher steady-state RNA level than before the switch. After adjusting for RNA level and CD4 T cell count, SI phenotype was an independent marker for progression to AIDS. Hence, phenotype determination will contribute to optimal staging of HIV-infected persons in addition to virus load measurements and CD4 T cell count.

Acquired Immunodeficiency Syndrome↗

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↗

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

Selective inhibition of syncytium-inducing and nonsyncytium-inducing HIV-1 variants in individuals receiving didanosine or zidovudine, respectively.

By studying changes in the clonal composition of HIV-1 populations during the first weeks of zidovudine (ZDV) treatment before the development of ZDV resistance-conferring mutations, we demonstrated previously a selective inhibition of nonsyncytium-inducing (NSI) HIV-1, even when present as coexisting population in individuals also harboring syncytium-inducing (SI) HIV-1. In this study, we observed the opposite in individuals receiving didanosine (ddI) treatment. In these individuals (n = 7) a median -0.98 log change (range -1.55-0.08) in infectious cellular SI load was observed, whereas the coexisting NSI load was only minimally affected (median -0.15 log, range -1.27-0.50; P = 0.03). The virus phenotype-dependent treatment responses were independent of the clonal composition of HIV-1 populations at baseline. Individuals treated with a combination of ZDV and ddI revealed an equal decline of both NSI and SI infectious cellular load (n = 4; NSI: median -1.55 log, range -2.19 to -1.45; SI: median -1.47 log, range -1.81 to -0.86; P = 0.56). To test the hypothesis that the previously reported optimal activation of ZDV and ddI in activated and resting T cells, respectively, in combination with the differential T cell tropism of NSI and SI HIV-1 is the basis for the observed virus phenotype specific efficacy of nucleoside analogs, we studied the effect of treatment with a protease inhibitor that does not require intracellular activation. Individuals receiving ritonavir (n = 4) indeed showed equal declines in NSI and SI infectious cellular load (NSI: median -2.37 log, range -2.59 to -2.16; SI: median -2.82 log, range -3.14 to -2.50; P = 0.25). Our data suggest HIV-1 phenotype as an additional parameter in the design of optimal treatment regimens.

Animals↗

PubMed1997

[Zidovudine-resistant HIV strains in untreated intravenous drug users and homosexual men in Amsterdam infected in 1996].

OBJECTIVE: To gain insight into the spread of HIV strains with different sensitivities to antiretroviral drugs prescribed in the Netherlands. DESIGN: Prospective cohort study in intravenous drug users and homosexual men. SETTING: Amsterdam, the Netherlands. METHODS: HIV negative participants in the Amsterdam cohort studies among homosexual men and intravenous drug users are tested two to three times a year for HIV antibodies. The first positive serum sample of those who seroconverted was used to determine, on the basis of the nucleotide sequence of the reverse transcriptase gene of HIV, if viruses were present with a reduced sensitivity to reverse transcriptase inhibitors. RESULTS: In 1996, 17 new HIV infections occurred (8 in homosexual men and 9 in intravenous drug users). In two new infections in homosexual men HIV strains with reduced sensitivity to zidovudine were present.

Anti-HIV Agents↗

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

[AIDS; new developments. III. Predictive value of the quantity of HIV-RNA for the course of the HIV infection and the effect of the treatment].

Standardized tests to measure the quantity of HIV-RNA in blood have been available since early 1995. Individual differences in quantity of HIV-RNA in blood are determined mainly by differences in virus production. Most of the HIV production takes place in infected and activated CD4+ T lymphocytes. The concentration of HIV-RNA in plasma or serum is an important predictor of AIDS and death, in the early stage of the infection even the only one. High concentrations (> or = 10(4) HIV-RNA copies/ml) in the early stage of the infection increase the probability of AIDS from 2.5 to 5 times that with concentrations < 10(4) HIV-RNA copies/ml. The degree of reduction of the HIV-RNA concentration during anti-HIV therapy is of great predictive value for the clinical course. The percentage of persons in whom the amount of HIV-RNA decreases to below the limit of detectability is a good second indicator of a favourable prognosis. Consequently, anti-HIV treatment should be started as early as possible in the infection, and not postponed until the first symptoms of immunodeficiency occur; only then can the virus production be kept at a minimal level as early and as long as possible. The current guideline reads: determination of HIV-RNA concentrations in serum or plasma should be part of the standard clinical practice in monitoring HIV-infected persons. Treatment is started as soon as occasioned by the quantity of HIV-RNA (limit: 10,000 copies/ml), the CD4+ cell count (limit: 500 x 10(6)/l) or the onset of HIV-related symptoms. The quantity of HIV-RNA should diminish substantially during the first three months of treatment. If this is the case, one checkup every three months will suffice. If the HIV-RNA concentration does not decrease sufficiently, resistance or poor compliance may be involved.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Risk of iatrogenic human immunodeficiency virus infection through transfusion of blood tested by inappropriately stored or expired rapid antibody assays in a Zambian hospital.

BACKGROUND: The purpose of this study was to estimate the risk of human immunodeficiency virus (HIV) infection via the transfusion of blood tested by inappropriately stored or expired rapid antibody assays in Zambia. STUDY DESIGN AND METHODS: Surgical patients (n = 370) were tested with antibody assays (HIV-spot and HIV 1+2) that had expired 3 to 6 months previously. Blood donors (n = 211) were tested by inappropriately stored but non-expired HIV-spot assay. Serum samples from both groups were retested with enzyme immunoassays, and the seropositivity of samples was confirmed by immunoblotting. RESULTS: Seroprevalence in surgical patients and blood donors was 19.8 and 11.6 percent, respectively. Sensitivity and specificity of HIV-spot (expired) were 88.2 and 98.1 percent; those of HIV 1+2 (expired) were 82.1 and 94.7 percent; and those of HIV-spot (non-expired) were 91.7 and 98.8 percent, respectively. The risk of HIV infection via the transfusion of blood tested by HIV-spot (expired), HIV-spot (nonexpired), or HIV 1+2 (expired) was calculated to be 1.4, 1.0, and 3.2 percent, respectively. CONCLUSION: Manufacturers of the HIV-spot and HIV 1+2 assays claim sensitivity and specificity of 98.8 and 100 percent and 100 and 99.5 percent, respectively. In this study, sensitivity and specificity were 11 to 18 percent lower. Moreover, in-date reagents also performed less well than the manufacturers claimed, but the worst results were with expired or improperly stored reagents. According to the manufacturers of HIV-spot and HIV 1+2, the risk of HIV infection would be 0.2 and 0 percent, respectively. However, the risk of contracting HIV through transfusion is at least six times higher than expected.

AIDS Serodiagnosis↗

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

High-dose interferon-alpha2a exerts potent activity against human immunodeficiency virus type 1 not associated with antitumor activity in subjects with Kaposi's sarcoma.

Anti-human immunodeficiency virus type 1 (HIV-1) activity was assessed in HIV-1-infected homosexual and bisexual men receiving 18-36 MIU/day of recombinant interferon (IFN)-alpha2a for Kaposi's sarcoma (KS). The median baseline HIV-1 RNA level was 4.99 log10 copies/mL. Seventeen subjects (68%) showed an RNA decline > or = .5 log10/mL, with a maximum at week 4 (median decline = 1.91, range = 3.64-1.15; P = .0007), after which RNA levels stabilized. Eight subjects (32%) with lower median initial CD4+ T cell counts (60 vs. 350 x 10(6)/L; P = .01) did not show RNA responses. Neither RNA nor KS responses were negatively affected by IFN-alpha2a dose modifications. Anti-HIV responses of KS responders (n = 15) and nonresponders (n = 10) did not differ. High-dose IFN-alpha can exert potent anti-HIV activity that is not associated with anti-KS activity.

AIDS-Related Opportunistic Infections↗

PubMed1997

Temporal relationship between human immunodeficiency virus type 1 RNA levels in serum and cellular infectious load in peripheral blood.

Cross-sectional analysis of 252 paired serum and peripheral blood mononuclear cell (PBMC) samples derived from 54 human immunodeficiency virus type 1 (HIV-1)-infected persons revealed a correlation between HIV-1 RNA load in serum and infectious load in peripheral CD4 T cells after 18 months of follow-up and before an AIDS diagnosis (Pearson's correlation coefficient [r(p)] = .71, P < .001) and during antiviral treatment (r[p] = .78, P < .001). To gain insight into the temporal relationship between both measures of virus load, longitudinally obtained samples from 23 persons with various clinical courses (slow or rapid disease progression, long-term survival) and 22 persons undergoing antiviral therapy (zidovudine or didanosine, or both, or ritonavir) were analyzed. In general, the kinetics of changes in both measures of virus load were similar in the natural course of infection (78% of study participants) and during treatment (82% of participants). These findings suggest that PBMC and serum represent closely related, if not the same, viral compartments.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Overshoot of HIV-1 viraemia after early discontinuation of antiretroviral treatment.

OBJECTIVE: To determine whether, as predicted by predator-prey dynamics, early withdrawal of antiretroviral therapy, i.e. when the number of CD4+ lymphocytes is still elevated, results in an overshoot of HIV-1 viraemia due to infection of increased numbers of available target cells at that time. DESIGN AND METHODS: Five HIV-1-infected individuals were identified who discontinued antiretroviral therapy for various reasons after 8-19 days, and from whom stored serum samples obtained before, during, and shortly after treatment were available for measurement of HIV-1 RNA load. A mathematical model was designed to assess whether increased target cell availability could quantitatively explain the clinical observations. RESULTS: After therapy withdrawal, increases in the HIV-1 RNA load to levels exceeding pretreatment values by log10 0.6-1.5 copies/ml were observed after 2-17 days in all four of the individuals who had treatment-induced increases in CD4+ cell counts at the time of therapy withdrawal. Increases in viraemia were maximal within a few days, and subsequently seemed to wane until the pretreatment equilibrium between virus and its target cells was attained. Mathematical modelling confirms that these transient increases in viraemia can be explained by increased availability of target cells at the time of therapy withdrawal. CONCLUSIONS: Transient rises in HIV-1 viraemia do occur following early therapy withdrawal. These rises especially warrant consideration in short-term antiretroviral regimens for prevention of mother-to-child transmission, as are being studied in developing countries, since they could result in an increased transmission risk during the post-partum period through breast-feeding. This possibility needs to be investigated urgently.

Anti-HIV Agents↗

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↗

PubMed1996

T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover.

Progression to acquired immunodeficiency syndrome (AIDS) has been related to exhaustion of the regenerative capacity of the immune system resulting from high T cell turnover. Analysis of telomeric terminal restriction fragment (TRF) length, a marker for cellular replicative history, showed that CD8(+) T cell TRF length decreased but CD4(+) T cell TRF length was stable during the course of human immunodeficiency virus type-1 (HIV-1) infection, which was not explained by differential telomerase activity. This observation provides evidence that turnover in the course of HIV-1 infection can be increased considerably in CD8(+) T cells, but not in CD4(+) T cells. These results are compatible with CD4(+) T cell decline in HIV-1 infection caused by interference with cell renewal.

Acquired Immunodeficiency Syndrome↗