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Biomedical subjects

H Schuitemaker

Publications and source records attributed to H Schuitemaker.

At least 55 records · Page 3Linked to original sources
PubMed1998

The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy.

OBJECTIVE: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. DESIGN: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. METHODS: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. RESULTS: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. CONCLUSIONS: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.

Anti-HIV Agents↗
PubMed1998

Alternative multidrug regimen provides improved suppression of HIV-1 replication over triple therapy.

OBJECTIVE: To compare the viral suppression of two antiretroviral regimens using three drugs or five drugs. DESIGN: Two open-label studies using a three-drug (zidovudine, lamivudine and ritonavir) and a five-drug regimen (zidovudine, lamivudine, abacavir, indinavir and nevirapine) in study-drug-naive patients, except for one in the five-drug study. METHODS: Participants with > or = 10 000 HIV-1 RNA copies/ml in plasma at baseline were compared by means of Kaplan-Meier curves for time to < 50 copies/ml, as well as linear regression analysis for the first phase of decline using log-transformed copy numbers. RESULTS: The elimination rate constants for HIV-1 RNA in 15 participants of the three-drug study were compared with nine participants of the five-drug study. The level of < 50 copies/ml was reached earlier when using the five-drug than when using the three-drug regimen (P log rank = 0.0005): median time to reach this level was 4 weeks and 12 weeks, respectively. No differences were found in HIV-1 RNA elimination rate constants in the first 2 weeks after the initiation of therapy. When the viral load declines were calculated from day 2 onwards, adjusting for differences in pharmacological delay of the drugs used, again no differences in early viral load decline were found between the two regimens. CONCLUSION: With the five drugs used in this study, the median time to reach < 50 HIV-1 RNA copies/ml was 8 weeks shorter than with the three-drug regimen. This finding shows that suppression of viral load in HIV-infection by standard triple-drug therapy can be improved upon.

Adult↗
PubMed1998

Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study.

BACKGROUND: Highly active antiretroviral therapy (HAART) has led to health benefits for patients infected with HIV-1. However, long-term use of multidrug regimens is difficult to sustain. Simplifying antiretroviral treatment regimens would increase patients' adherence and minimise toxicity. We investigated the feasibility of a strategy of induction therapy followed by maintenance therapy with HAART in a randomised open-label study. METHODS: From March, 1997, we enrolled patients infected with HIV-1 with at least 200 CD4 cells/microL, at least 1000 HIV-1 RNA copies/mL in plasma, and no previous exposure to antiretroviral drugs. After 26 weeks of induction therapy (stavudine, lamivudine, saquinavir, and nelfinavir) patients were randomly allocated maintenance therapy (either stavudine and nelfinavir or saquinivir and nelfinavir) or prolonged induction therapy (if the plasma HIV-1 RNA concentration at weeks 24 and 25 was <50 copies/mL). FINDINGS: In February, 1998, we discontinued randomisation after an interim analysis. 62 patients had been enrolled. 39 (91%) of the 43 patients who were followed up for at least 26 weeks had an undetectable plasma HIV-1 RNA concentration at week 16. At week 26, 31 patients were randomly allocated treatment. Of these patients 25 had a total follow-up of at least 36 weeks. At week 36, a higher proportion of patients on maintenance therapy (nine [64%] of 14) had a detectable HIV-1 RNA than patients on prolonged induction therapy (one [9%] of 11, p=0.01). The initial virion-clearance rate during induction therapy was higher in five patients on maintenance therapy with a sustained undetectable plasma HIV-1 RNA concentration than in nine patients with recurrence of a detectable plasma HIV-1 RNA concentration at week 36 (0.35 vs 0.19 per day, respectively; p=0.0008). INTERPRETATION: The induction regimen provided a rapid suppression of viral replication to below 50 copies/mL. However, suppression was not sustained in a considerable number of patients who went onto maintenance therapy. It is currently inadvisable to continue attempts at moving from induction to maintenance therapy in day-to-day practice.

Adult↗
PubMed1998

Efficient inhibition of both syncytium-inducing and non-syncytium-inducing wild-type HIV-1 by lamivudine in vivo.

OBJECTIVE: To determine the effect of lamivudine (3TC) on syncytium-inducing (SI) and non-SI (NSI) HIV-1 populations in vivo. DESIGN: Responses in virus load and 3TC resistance in 40 3TC-treated subjects were analysed in relation to the presence or absence of SI HIV-1 variants. METHODS: Peripheral blood samples were collected at regular intervals from 40 HIV-1-infected subjects during 3TC treatment. Virus isolates obtained at the start of treatment were typed for SI-capacity by coculture with MT-2 cells. Changes in levels of viral RNA in plasma were determined by quantitative reverse transcriptase PCR. The relative amount of wild-type and mutant virus at codon 184, associated with HIV resistance to 3TC, was determined using a primer-guided nucleotide incorporation assay after amplification of part of the reverse transcriptase gene. In five subjects the frequency of productively infected CD4+ cells with SI or NSI variants was determined in relation to codon 184 genotype. RESULTS: Twenty-six subjects harboured only NSI variants at baseline, whereas 14 subjects also harboured SI variants. Although baseline plasma viral RNA load and CD4 cell counts were different between the two groups, no differences in the response to 3TC therapy were observed for these parameters. In-depth analysis of five subjects showed that the kinetics of virus load changes and emergence of 3TC resistance mutations were similar in plasma and cells, and comparable for the SI and NSI populations present in one individual. CONCLUSIONS: These data show that, in contrast to didanosine and zidovudine, the pressure exerted by 3TC is similar for SI and NSI M184 populations.

Anti-HIV Agents↗
PubMed1998

The role of a stromal cell-derived factor-1 chemokine gene variant in the clinical course of HIV-1 infection.

BACKGROUND: A G-to-A transition in the 3' untranslated region (UTR) of stromal cell-derived factor (SDF)-1 gene (SDF1-3'A) has recently been described, which in the homozygous state was associated with delayed disease progression. OBJECTIVE: To analyse the effect of the SDF-1 polymorphism on AIDS-free survival and survival after AIDS diagnosis, also in relation to viral phenotype. DESIGN: Retrospective longitudinal study among 344 homosexual HIV-1-infected men. RESULTS: A more rapid progression to AIDS (Centers for Disease Control and Prevention 1993 definition) was observed in SDF1-3'A/3'A subjects than in wild-type (SDF1-wt/wt) subjects (relative hazard, 1.75; P = 0.07). Using death as an endpoint, accelerated progression was no longer observed (relative hazard, 0.93; P = 0.84), suggesting a late protective effect of the SDF1-3'A/3'A genotype. Indeed, survival after AIDS diagnosis was significantly delayed in SDF1-3'A/3'A subjects (relative hazard, 0.40; P = 0.02). No effect of the SDF1-3'A/wt genotype on disease progression was observed. Interestingly, a higher frequency of Kaposi's sarcoma was observed as the AIDS-defining event among SDF1-3'A/3'A (40.0%) and SDF1-3'A/wt (30.6%) subjects than in SDF1-wt/wt subjects (17.0%). At the end of the study the total frequency of syncytium-inducing (SI) HIV-1 variants was lower in SDF1-3'A/3'A subjects (22.2%) than in SDF1-3'A/wt (32.5%) and SDF1-wt/wt subjects (40.5%), although not significantly. SDF-1 genotype did not influence the rate of evolution to SI HIV-1. Progression to AIDS after the emergence of SI HIV-1 was accelerated in SDF1-3'A/3'A subjects compared with the SDF1-wt/wt genotypic group (relative hazard, 4.04; P = 0.06). CONCLUSIONS: In our study group, homozygosity for a G-to-A transition in the 3' UTR of SDF-1 is associated with an accelerated progression to AIDS but a subsequent prolonged survival after AIDS diagnosis.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Proliferation-dependent replication in primary macrophages of macrophage-tropic HIV type 1 variants.

We previously demonstrated that completion of reverse transcription in macrophages inoculated with the HIV-1 Ba-L variant was established only in the subpopulation of cells with proliferative capacity. In our present study we further extended this observation with three additional HIV-1 isolates, being the macrophage-tropic ADA strain and two primary macrophage-tropic HIV-1 variants isolated from cerebrospinal fluid and from bronchoalveolar lavage from AIDS patients. On inoculation, irrespective of the virus variant used, elongated reverse transcription products could be demonstrated only in macrophages that had proliferated during inoculation as evidenced by the incorporation of bromodeoxyuridine (BrdU), a thymidine analog. The presence of newly synthesized early products of reverse transcription also in the BrdU-negative fraction indicated that viral entry is not disturbed in nondividing cells. Our data indicate that the process of reverse transcription is dependent on cellular conditions that coincide with cell proliferation, and therefore that HIV-1 replication is restricted to cells with proliferative potential.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Virus validation of pH 4-treated human immunoglobulin products produced by the Cohn fractionation process.

To assess the virus reducing capacity of Cohn's cold ethanol fractionation process for the production of intravenous (IVIg) and intramuscular (IMIg) immunoglobulin products, and treatment of these products at pH 4, a validation study of virus removal and/or inactivation was performed using both lipid-enveloped viruses [human immunodeficiency virus (HIV), bovine viral diarrhoea virus (BVDV) and pseudorabies virus (PSR)], and non-lipid-enveloped viruses [(simian virus 40 (SV40) and encephalomyocarditis virus (EMC)]. For the cold ethanol fractionation process, overall reduction factors of 3.0 logs, > or = 2.6 (< 5.5) logs, 4.6 logs, 5.8 logs and > or = 2.6 (< 6.2) logs were found for HIV, BVDV, PSR, SV40 and EMC, respectively. For all tested viruses the precipitation of fraction III from fraction II + III was the most effective step. From the overall reduction factors it appears that cold ethanol fractionation, although capable of reducing viral infectivity to a significant extent, is not sufficient to meet the requirements of regulatory bodies for viral safety of immunoglobulin products. However, pH 4 treatment contributes effectively to the viral safety of the final products. Treatment at pH 4.05 and 37 degrees C for 16 h, as is applied to IVIg, yields reduction factors of > or = 8.4 logs, > or = 4.0 logs, > or = 7.1 logs, 4.8 logs and 1.4 logs for HIV, BVDV, PSR, SV40 and EMC, respectively. The effectiveness of this process step could be enhanced by extending incubation to 40 h at pH 4.25 compared to 16 h at pH 4.05. The extended incubation, as applied in the production of IMIg, yields a reduction of infectivity of SV40 by > or = 5.5 (< 8.0) logs and of EMC by > or = 4.1 (< 7.1) logs. Storage of IMIg, which is formulated as a solution, at 2-8 degrees C also contributes to virus safety. For storage periods of 8 weeks or longer, reduction factors of 2 to 6 logs were found for all viruses, except for BVDV which remained unaffected. These data indicate that the production processes for IVIg and IMIg as described here have sufficient virus reducing capacity to achieve a high margin of virus safety.

Animals↗
PubMed1998

Chemokine receptors and the clinical course of HIV-1 infection.

For several years, the cellular basis behind the differences in HIV-1 tropism and the species specificity of HIV-1 has remained unclear. Since the discovery that chemokine receptors are essential cofactors for entry of HIV-1 into cells, tremendous progress has been made in the understanding of the role played by co-receptors in HIV-1 biological variability, HIV-1 transmission and AIDS pathogenesis.

HIV Infections↗
PubMed1998

Role of CCR2 genotype in the clinical course of syncytium-inducing (SI) or non-SI human immunodeficiency virus type 1 infection and in the time to conversion to SI virus variants.

The effect of a valine to isoleucine switch in the CCR2 first transmembrane domain (CCR2 64I) on the clinical course of human immunodeficiency virus type 1 (HIV-1) infection was analyzed in relation to the presence or absence of syncytium-inducing (SI) HIV-1 variants. Compared with persons with a wild-type genotype for CCR2 and CCR5, subjects with a CCR2-64I/+ or 64I/64I (but CCR5 wild-type homozygous genotype) had significantly delayed disease progression (relative hazard, 0.66; 95% confidence interval, 0.44-0.99) with a 1. 5-fold slower CD4 T lymphocyte decline and a 1.2-fold lower RNA virus load. The delay in disease progression was more pronounced when only non-SI (NSI) HIV-1 variants were present and was not observed after conversion to SI HIV-1 in CCR2-64I/+ persons. In CCR2-64I/+ subjects, a higher conversion rate to and a higher prevalence of SI HIV-1 was observed. These findings suggest that the mechanism of action of the CCR2 polymorphism is mediated via CCR5-restricted NSI HIV-1 variants.

Cells, Cultured↗
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↗
PubMed1998

Characteristics of primary infection of a European human immunodeficiency virus type 1 clade B isolate in chimpanzees.

The aim of the study was to select, from a panel of candidate European human immunodeficiency virus type 1 (HIV-1) clade B primary virus isolates, one isolate based on replication properties in chimpanzee peripheral blood mononuclear cells (PBMC). Secondly, to evaluate the in vivo kinetics of primary infection of the selected isolate at two different doses in two mature, outbred chimpanzees (Pan troglodytes). Four different low passage, human PBMC-cultured 'primary' HIV-1 isolates with European clade B consensus sequence were compared for their ability to replicate in vitro in chimpanzee versus human PBMC. The isolate which yielded the highest titre and most vigorous cytopathic effect in chimpanzee PBMC was evaluated for coreceptor usage and chosen for evaluation in vivo. Only the HIV-1Han2 isolate replicated in chimpanzee PBMC in vitro at detectable levels. This isolate was demonstrated to utilize CCR4, CCR5 and CXCR4 coreceptors and could be inhibited by beta-chemokines. Infection of chimpanzees was demonstrated by viral RNA and DNA PCR analysis, both in plasma as well as in PBMC and lymph node cells as early as 3 weeks after inoculation. Antibodies developed within 6 weeks and continued to increase to a maximum titre of approximately 12800, thereafter remaining in this range over the follow-up period of 2 years. Compared to cell line-adapted HIV-1 isolates there were slight but no dramatic differences in the kinetics of infection of chimpanzees with this particular primary isolate.

Animals↗
PubMed1998

Infectious cellular load in human immunodeficiency virus type 1 (HIV-1)-infected individuals and susceptibility of peripheral blood mononuclear cells from their exposed partners to non-syncytium-inducing HIV-1 as major determinants for HIV-1 transmission in homosexual couples.

To study risk factors for homosexual transmission of human immunodeficiency virus type 1 (HIV-1), we compared 10 monogamous homosexual couples between whom transmission of HIV-1 had occurred with 10 monogamous homosexual couples between whom HIV-1 transmission had not occurred despite high-risk sexual behavior. In the group of individuals who did not transmit virus, peripheral cellular infectious load was lower and the CD4+ T-cell counts were higher than in the group of transmitters. HIV-1 RNA levels in serum did not differ between transmitters and nontransmitters. Compared with peripheral blood mononuclear cells (PBMC) from normal healthy blood donors, 8 of 10 nonrecipients and only 3 of 8 recipients had PBMC with reduced susceptibility to in vitro infection with non-syncytium-inducing (NSI) HIV-1 variants isolated from either their respective partners or an unrelated individual. No difference in susceptibility was observed for infection with a syncytium-inducing variant. Among the individuals who had PBMC with reduced susceptibility, five nonrecipients and one recipient had PBMC that were equally or even less susceptible to NSI variants than PBMC that had low susceptibility and that were derived from healthy blood donors that were heterozygous for a 32-bp deletion in the CCR5 gene (CCR5 delta32). Three of these individuals (all nonrecipients) had a CCR5 delta32 heterozygous genotype themselves, confirming an association between low susceptibility to NSI variants and CCR5 delta32 heterozygosity. All three recipients with less susceptible PBMC had partners with a high infectious cellular load; inversely, both nonrecipients with normally susceptible PBMC had partners with a very low infectious cellular load. These results suggest that a combination of susceptibility of target cells and inoculum size upon homosexual exposure largely determines whether HIV-1 infection is established.

Adult↗
PubMed1998

Analysis of the temporal relationship between human immunodeficiency virus type 1 quasispecies in sequential blood samples and various organs obtained at autopsy.

We studied the temporal relationship between human immunodeficiency type 1 (HIV-1) quasispecies in tissues and in peripheral blood mononuclear cells (PBMC) of infected individuals. Sequential PBMC and tissue samples from various organs obtained at autopsy from three patients who died of AIDS-related complications were available for analysis. Biological HIV-1 clones were isolated from PBMC samples, and cellular tropism and syncytium-inducing (SI) capacity were determined. Genomic DNA was isolated from 1 cm3 of organ tissue, and proviral DNA was amplified by means of PCR and cloned with the PGEM-T vector system. A 185-bp region encompassing the third variable domain of the virus envelope, known to influence HIV-1 biological properties, was sequenced. HIV-1 could be amplified from all PBMC and organ samples, except from liver tissue for two patients. Both SI and non-syncytium-inducing (NSI) genotypes could be detected in the different tissues. Tissue-specific quasispecies were observed in brain, lung, and testis. Lymphoid tissues, such as bone marrow, lymph node, and spleen, harbored several different variants similar to those detected in blood in the last PBMC samples. In general, only tissues in which macrophages are likely to be the main target cell for HIV-1 harbored NSI HIV-1 sequences that clustered separately. Both SI and NSI sequences that clustered with sequences from late-stage PBMC were present in other tissues, which may indicate that the presence of HIV-1 in those tissues is secondary to lymphocyte infiltration rather than to tissue tropism of HIV-1 itself. These data suggest that the viral reservoir may be limited, which will have important implications for the success of HIV-1 eradication.

Amino Acid Sequence↗
PubMed1998

Evolution of syncytium-inducing and non-syncytium-inducing biological virus clones in relation to replication kinetics during the course of human immunodeficiency virus type 1 infection.

To investigate the temporal relationship between human immunodeficiency virus type 1 (HIV-1) replicative capacity and syncytium-inducing (SI) phenotype, biological and genetic characteristics of longitudinally obtained virus clones from two HIV-1-infected individuals who developed SI variants were studied. In one individual, the emergence of rapidly replicating SI and non-syncytium-inducing (NSI) variants was accompanied by a loss of the slowly replicating NSI variants. In the other subject, NSI variants were always slowly replicating, while the coexisting SI variants showed an increase in the rate of replication. Irrespective their replicative capacity, the NSI variants remained present throughout the infection in both individuals. Phylogenetic analysis of the V3 region showed early branching of the SI variants from the NSI tree. Successful SI conversion seemed a unique event since no SI variants were found among later-stage NSI variants. This was also confirmed by the increasing evolutionary distance between the two subpopulations. At any time point during the course of the infection, the variation within the coexisting SI and NSI populations did not exceed 2%, indicating continuous competition within each viral subpopulation.

Amino Acid Sequence↗