摘要:

BackgroundTherapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown.In vitrostudies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers.MethodsRandomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies.ResultsThere were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60−−180min) insulin reached comparable levels (394 ± 13 versus 390 ± 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 ± 2.2 μM and the 2-h area under the curve was 13.5 ± 3.1 μM⋅h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 ± 1.2 to 9.2 ± 0.8 mg/kg⋅min per μ UI/ml (95% confidence interval for change, 3.7–6.1;P< 0.001) on indinavir (average decrease, 34.1 ± 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 ± 1.8 to 1.9 ± 0.9 mg/kg⋅min (P< 0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies.ConclusionsA single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundDendritic cells (DC) are target cells for HIV-1 and play a key role in antigen presentation and activation of T cells.ObjectiveTo characterize interdigitating DC in lymphoid tissue (LT) with regard to maturation, expression of cytokines and co-stimulatory molecules in HIV-1-positive patients.MethodsDC were characterized by immunohistochemistry and in situ imaging in LT from patients with acute HIV-1 infection (aHI), antiretroviral treated patients, long-term non-progressors/slow progressors with HIV-1 infection (LTNP/SLP), patients with AIDS, HIV-1-negative controls and patients with acute Epstein–Barr virus (EBV) infection.ResultsA significant increase of interdigitating DC expressing CD1a, S-100b, CD83 and DC-SIGN was found in LT from patients with aHI(P< 0.02). The co-stimulatory molecules CD80 and CD86 were, however, only partially upregulated and the complete parafollicular network found in acute EBV infection was not generated, despite increased expression of interleukins 1α, 1β, 12; interleukin 1α receptor antagonist; interferon α; and CD40 expression. LTNP/SLP and treated aviremic subjects had increased frequency of interdigitating DC, albeit lower than in aHI, and low expression of CD80 and CD86. In contrast, patients with AIDS had fewer DC and reduced cytokine expression in LT.ConclusionsIn the early phase of HIV-1 infection, there was a migration of DC to LT comparable to that found in acute EBV infection. The infiltration of DC in LT in acute EBV infection was accompanied by upregulation of CD80 and CD86 expression, which did not occur in aHI. This co-stimulatory defect in aHI may have an impact on the development of HIV-1-specific T cell immunity.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundProteasomes constitute the degradative machinery of the ubiquitin/adenosine triphosphate-dependent proteolytic pathway, which is involved in many cell functions, including immune response and apoptosis, and in HIV maturation and infectivity.ObjectiveTo examine whether proteasomes are targeted by antiretroviral agents.MethodsChymotrypsin-like, trypsin-like and peptidyl–glutamyl–peptide hydrolysing activities of purified human 26S and 20S proteasomes, the latter depleted or enriched in 11S regulator, were assayed after incubation with indinavir, lamivudine and zidovudine at 1–80 μM alone and in combination. To assess the drug effects on cellular functions regulated by proteasomes, the accumulation of ubiquitin-tagged proteins, the processing of the nuclear factor kappa B precursor p105, and the degradation of the inhibitor of nuclear factor kappa B, isoform alpha (IκBα) were evaluated by Western immunoblotting in Jurkat cells after incubation for 6 h with the drugs above.ResultsTrypsin-like and mostly chymotrypsin-like activities of purified 26S proteasome were inhibited by each drug from 10 to 80 μM, more by double combinations and mostly by the triple combination. The peptidyl–glutamyl–peptide hydrolysing activity of the 26S proteasome and the three peptidase activities of the 20S proteasome, depleted or enriched in 11S regulator, were unaffected. The accumulation of ubiquitin-tagged proteins, reduced IκBα degradation and p105 processing were appreciable in intact cells with the triple drug combination.ConclusionThe human 26S proteasome is a target of antiretroviral agents. This suggests that the antiviral action and some clinical and immunological benefits of combined antiretroviral therapy rely not only on its known effects on viral enzymes, but also on host cell components.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo identify and characterize cytotoxic T-cell (CTL) epitopes for HIV-1 clade E using eight known HLA-A*1101-restricted HIV-1 clade B epitopes.MethodsInduction of clade E-specific CTL was examined by stimulating peripheral blood mononuclear cells (PBMC) from clade E-infected Thai individuals with the clade E-specific peptide corresponding to the clade B epitopes. Cross-clade and clade-specific CTL recognition for these epitopes was analysed using CTL clones and bulk CTL specific for these epitopes. To clarify the presentation of these epitopes in HIV-1-infected T cells, CTL recognition for the clade E-specific and cross-clade epitopes was investigated using CD4CXCR4 cells infected with an HIV-1 clade E clone.ResultsThree epitopes, which are identical among clades A–E, were recognized as cross-clade CTL epitopes in both individuals. Clade B and E sequences corresponding to three epitopes were recognized as clade-specific epitopes in clade B-infected and clade E-infected individuals, respectively. In contrast, clade E-specific peptides corresponding to two other clade B epitopes failed to elicit clade E-specific CTL. CTL specific for the three cross-clade and three clade E-specific epitopes effectively lysed target cells infected with HIV-1 clade E virus.ConclusionsThese six epitopes are found to be processed naturally in HIV-1 clade E-infected cells. We show here that a strategy utilizing HIV-1 clade B epitopes is very useful for identifying clade E CTL epitopes.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectivesTo compare the T-cell responses to hepatitis C virus (HCV) and HIV in HIV-infected long-term non-progressors (LT-NP) and HIV-positive progressors co-infected with HCV and in HIV-negative HCV-infected patients.MethodsThree groups were studied: 10 HCV/HIV-infected LT-NP, 26 HCV/HIV-infected progressors and 13 HCV-infected/HIV-negative patients. Virus-specific CD4 and CD8 T-cell responses in peripheral blood were assessed by interferon (IFN)-γ Elispot assays using recombinant proteins (HIV-p24 and three HCV antigens) and 16 HIV or HCV HLA A3- and/or HLA A2-restricted cytotoxic T lymphocytes peptides. Statistical analysis was performed with non-parametric tests.ResultsIn addition to high T helper 1 (Th1) cell frequencies directed against HIV-p24, LT-NP had significantly (P< 0.05) higher frequencies of Th1 cells against HCV than the two other groups. No difference was observed between HIV-infected progressors and HIV-negative controls. Furthermore , HCV-specific CD4 and CD8 T cells were correlated in LT-NP (P= 0.006).ConclusionThus, independently of the HIV-related immune alterations, LT-NP of the HIV-infection might have an intrinsic capacity to develop strong Th1 cell responses to viruses, particularly HIV and HCV.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundThe treatment of HIV-1-infected patients with triple-drug combination therapy results in profound suppression of viral replication. In most therapy-naive patients plasma HIV-1-RNA levels (pVL) drop below the lower limit of quantification (LLQ) of currently used assays. In a large percentage of such patients, more sensitive assays provide evidence of residual viral replication. The question is whether more potent therapy can further suppress this residual replication.MethodsThirty control patients who, using very strict criteria, had not experienced virological failure during 3 years of standard therapy, were compared with 10 patients treated with a five-drug regimen, consisting of three different classes of antiretroviral drugs (alternative multidrug regimen). A modified ultrasensitive assay with an LLQ of 5 copies/ml was used to re-test plasma obtained at week 48 and at three timepoints at and around week 144.ResultsAt weeks 48 and 144 pVL could be quantified significantly more frequently in control patients than in patients using the alternative multidrug regimen (week 48: 42 versus 0% with quantifiable pVL,P= 0.017; week 144: 60 versus 14% with at least one quantifiable pVL,P= 0.036, respectively). A low baseline CD4T cell count was predictive of quantifiable pVL in control patients, but not in alternative multidrug patients.ConclusionThis proof-of-principle study demonstrates that the use of an alternative multidrug regimen results in stronger long-term suppression of pVL compared with clinically successful treatment with standard therapy.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

ObjectiveTo assess the respective value of phenotype versus genotype versus standard of care for choosing antiretroviral therapy in patients failing protease inhibitor-containing regimens.MethodsPatients with plasma HIV-1 RNA exceeding 1000 copies/ml were randomly allocated to phenotyping, genotyping, or standard of care.ResultsFive-hundred and forty-one patients were randomized, 190 to phenotyping, 192 to genotyping and 159 to standard of care. The baseline median CD4 cell count (280 × 106cells/l), the plasma HIV-1 RNA level (4.3 log10copies/ml), and the number of drugs previously received (n = 6) were similar in the three arms. More patients in the standard-of-care arm received at least three new drugs (55% versus 20% in the other arms;P< 0.001) and a regimen containing drugs from the three different classes. Plasma HIV-1 RNA was < 200 copies/ml at week 12 in 35% of patients in the phenotyping arm, 44% in the genotyping arm and 36% in the standard-of-care arm (phenotyping versus standard of care,P= 0.918; genotyping versus standard of care,P= 0.120). In a secondary analysis of 179 patients experiencing a first protease inhibitor failure, the percentage of patients achieving HIV-1 RNA < 200 copies/ml was significantly higher in the genotyping arm (65%) than in the phenotyping (45%) and the standard-of-care arms (45%) (genotyping versus standard of care,P= 0.022).ConclusionsOverall, resistance assays did not demonstrate benefit over standard of care. In patients with the most limited protease inhibitor experience, a significant benefit was observed in the genotyping arm.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

BackgroundToxicity is the most important reason for premature switching of highly active antiretroviral therapy (HAART). In order to optimize the benefit–risk ratio of HAART, guidelines for toxicity management are needed.ObjectiveAn observational cohort study to estimate the incidence and identify determinants of toxicity-driven switches on second-line HAART after having switched first-line HAART despite successful viral suppression.MethodsPatients were selected from those in the ATHENA cohort (n = 2470) who switched the initial HIV protease inhibitor (PI)-containing HAART while plasma HIV-1 RNA was ⩽ 500 copies/ml (n = 775). One-year cumulative incidences of subsequent toxicity-driven switches and adjusted relative risks (RR) for potential determinants were calculated.ResultsThe 1-year cumulative incidence of toxicity-driven switches of the second regimen was 24% [95% confidence interval (CI), 21–28], mostly because of gastrointestinal toxicity and neuropathy. Those who had switched from first HAART because of toxicity were at an increased risk of a recurrent toxicity-driven switch (RR, 2.5; 95% CI, 1.7–3.5). Switching from PI to nevirapine while continuing the other antiretroviral drugs was more protective against a subsequent switch because of further toxicity than changing to another PI-containing regimen (RR, 0.2; 95% CI, 0.1–0.6).ConclusionsAs for first-line HAART, toxicity is responsible for the majority of switches during second-line HAART. Prior switching for toxicity increased the risk of having to switch the subsequent regimen for toxicity, but this risk is reduced when switching to nevirapine rather than to an alternative PI. The latter should be taken into account when designing toxicity-management guidelines.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Objectives and designTo investigate the clinical consequences of occasional and short (⩽ 3 months) treatment interruptions in patients having initiated highly active antiretroviral therapy (HAART). Data from the prospective Swiss HIV Cohort Study were used.MethodsFour different endpoints [death, Centers for Disease Control and Prevention (CDC) stages B and C, and CD4 cell count increase ⩾ 50 × 106/l] were studied in relation to the number of interruptions that occurred. In order to focus on short interruptions exclusively, observations of patients with a treatment interruption of > 3 months were censored. The CD4 cell count and viraemia were treated as time-dependent variables because of the importance of these factors when an interruption occurs.ResultsBetween 1 January 1996 and 31 October 2000, 4720 Swiss HIV Cohort Study participants initiated HAART, which was interrupted at least once by 1299 participants. The main reasons for the interruptions were social factors. Interruptions did not increase significantly the risk of HIV-associated morbidity and mortality, except for a marginally increased risk for a CDC stage C event after the first interruption. The first interruption decreased significantly the likelihood of increasing the CD4 cell count. Subsequent interruptions had no further significant effect. High CD4 cell count and low viraemia, assessed as baseline and as longitudinal variables, were associated with a decreased risk of clinical progression.ConclusionsOccasional treatment interruptions of < 3 months neither worsen nor improve disease outcome on an average term (3–4 years). Our results suggest that interruptions might be non-risky, particularly when viraemia is low and CD4 cell count is high. These results require confirmation.

ISSN:0269-9370    

出版商:OVID    

年代:2002

数据来源: OVID