摘要:

Objective:Using SCID-Hu mice models andin vitroculture systems, it has been shown that syncytium inducing/CXCR4 using (X4) HIV-1 variants affect thymic function through infection and killing of CXCR4 thymocytes. The effect of X4-emergence on naive, memory and effector T-cell subset kineticsin vivois, however, not known.Design:Prospective cohort study.Methods:Analysis of changes in naive, memory and effector CD4 and CD8 T-cell numbers and cell division before and after the emergence of X4 variants.Results:Significantly lower numbers of CD4 T cells in patients with X4 variants (n = 18) compared to patients with non-syncytium inducing/CCR5 using variants (n = 74) were due to increased loss of naive and CD27 memory CD4 T cells. In addition, emergence of X4 variants was associated with a small but significant decline in naive CD8 T-cell numbers and increased proportions of dividing CD4 and CD8 naive, memory and effector T cells.Conclusion:Loss of naive T cells may suggest thymic dysfunction, however, such an effect would explain only part of the accelerated naive CD4 T-cell decline because of the longevity of naive T cells. Our data suggest that the accelerated naive CD4 T-cell decline induced by X4 variants is caused mainly by increased death and recruitment to the memory compartment of these cells.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To identify mechanisms of resistance to HIV-1 infection in exposed uninfected individuals.Design:We examined in-vitro cell susceptibility to HIV-1 infection in highly exposed Vietnamese intravascular drug users (IDU) who, despite a history of more than 10 years of drug use and a high prevalence of other blood-borne viral infections, remain apparently HIV uninfected.Methods:Forty-five exposed uninfected IDU and 50 blood donors were included in the study. Peripheral blood mononuclear cells (PBMC) or CD4 cell susceptibilities to HIV infection were evaluated using three HIV-1 isolates with different tropisms. Polymerase chain reaction analysis of HIV-1-DNA replication intermediates was used to characterize the restriction of HIV-1 replication in CD4 cells. Homologous CD8 cells were mixed with infected CD4 cells to evaluate their role in virus suppression.Results:We observed a relative resistance to PBMC infection with HIV-1 in 21 out of 45 exposed uninfected IDU, but only in five out of 50 unexposed controls (P< 0.001). PBMC resistance was related either to an inhibition of HIV-1 replication in CD4 cells or to CD8 cell-mediated viral suppression. HIV-1 replication in CD4 cells was restricted at the early stages of the viral cycle.Conclusion:Reduced PBMC susceptibility to HIV-1 infection was associated with resistance to infection in exposed uninfected IDU. Distinct mechanisms are involved in in-vitro resistance and may contribute to the apparent protection from HIV-1 transmission in this systemically exposed population.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:HIV-infected adults with lipodystrophy, characterized by excess accumulation of intra-abdominal adipose tissue (IAT), showed impaired growth hormone (GH) secretion. Data are lacking in paediatric lipodystrophy with the same features.Methods:Twenty-five pubertal HIV-infected children were assessed for GH response (GH-AUC0–120min) to arginine + GHRH testing, insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP-3), insulin, glucose, cholesterol, triglycerides, free fatty acids and nitric oxide levels. Body composition and IAT content were evaluated by dual-energy x-ray-absorptiometry and magnetic resonance imaging. An excess accumulation of IAT was defined as a value > 41 cm2. Differences between children with (V+) and without (V–) excess IAT were assessed by non-parametric tests and multivariate analysis.Results:Ten V+ (mean IAT, 82.5 cm2) and 15 V– (mean IAT, 26.8 cm2) were identified; they were similar for age (13.8 versus 14.8 years), body mass index (20.2 versus 19.5 kg/m2), male : female ratio (3/7 versus 8/7), months on highly active antiretroviral therapy (54.5 versus 55 months). V+ showed lower GH-AUC0–120min(16.4 versus 31.6 μg⋅h/l;P= 0.002), lower IGF-1 concentrations (384 versus 515 ng/ml;P= 0.03) and higher insulin levels (17.8 versus 10.5 μIU/ml;P= 0.01) than V–. V+, as compared to V–, showed lower lean mass (total,P= 0.025; arms,P= 0.024; legs,P= 0.008) and higher fat mass (total,P= 0.0038; arms,P= 0.028; trunk,P <0.0001). Lipid profile and glucose, IGFBP-3, nitric oxide and free fatty acids levels were similar in the two groups. GH-AUC0–120mincorrelated negatively with IAT content and insulin levels.Conclusion:Impaired GH secretion is detectable in pubertal children with increased visceral adiposity and hyperinsulinemia. GH therapy should be considered in lipodystrophic HIV-infected children with excess IAT.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:JC virus (JCV) is ubiquitous among the general population. However, only individuals with severely impaired immunity, mainly AIDS patients, develop progressive multifocal leukoencephalopathy (PML). Here, we examined the role of specific CD4 T cells in the control of JCV infection.Methods and design: JCV-specific CD4 T-cell responses were investigated by assaying peripheral blood mononuclear cell proliferation in response to the purified virus. Four groups of individuals without PML were examined: 14 HIV-seronegative healthy donors and 25 HIV-infected patients without PML, separated into urinary JCV excretors (active infection) and non-excretors, according to JCV PCR on urine. Two groups of patients with PML were also studied: 14 HIV-infected patients with active PML; and 10 PML survivors on effective and prolonged antiretroviral therapy. All of the patients were PCR-positive for JCV in the cerebrospinal fluid at the time of diagnosis of PML.Results:No significant anti-JCV CD4 T-cell proliferation was found in any of the non-excretors tested. All nine healthy donors and seven of the 13 non-PML HIV-infected patients with urinary JCV excretion had positive JCV-specific CD4 T-cell responses. No significant response was found in the 14 patients with active PML, while nine of the 10 PML survivors had positive responses. Restoration of JCV-specific CD4 T-cell responses was associated with JCV clearance from the cerebrospinal fluid.Conclusion:JCV-specific CD4 T-cell responses appear to play a critical role in the control of JCV infection, preventing PML development. Such responses can be restored in PML survivors following effective and prolonged antiretroviral therapy.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:HIV-2 can use a broader range of co-receptors than HIV-1in vitro, and is less dependent on CD4 for infection. The aim of this study was to detect productive HIV-2 infection in the brain and investigate whether HIV-2 has an expanded tropism for brain cellsin vivo, in comparison with HIV-1, which productively infects macrophages/microglia.Design:Brain samples taken at autopsy from eight patients who died from AIDS, six HIV-2 and two HIV-1/HIV-2 dually seropositive, with HIV encephalitis (HIVE), collected in Abidjan, Côte d'Ivoire in 1991, were examined for the presence and localization of productive HIV-2 infection.Methods:Using immunohistochemistry, the presence of HIV-2 p26 in formalin-fixed, wax-embedded brain tissue sections was investigated. Double-staining with glial fibrillary acidic protein (GFAP), CD45- and CD68-specific antibodies was performed to identify infected cell types.Results:HIV-2 p26 was detected in brain tissue from four of the HIV-2 cases and one of the dually infected individuals. The productively infected cells were either microglia or infiltrating macrophages.Conclusions:The productively infected cells in the brains of HIV-2 infected individuals are macrophages/microglia. No evidence was found for productive infection of astrocytes, neurons or oligodendrocytes. Thus, the broaderin vitrocell tropism, promiscuous coreceptor usage and relative independence of CD4 by HIV-2 compared to HIV-1 does not broaden its range of target cells in the brain.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Introduction:Epidemiological data demonstrate an association between hepatitis G virus (HGV) co-infection and improved survival of HIV-positive individuals. However, the mechanism by which HGV affects progression of HIV disease remains unclear. As down-regulation of CC chemokine receptor 5 (CCR5) delays HIV progression, we investigated whether CCR5 expression is altered by exposure of lymphocytes to HGV proteins.Methods:A cross-sectional analysis of CCR5 expression was carried out on CD4 and CD8 T lymphocytes of 11 HGV-positive and 12 HGV-negative persons, who were homozygous for the CCR5 wild-type gene. Binding of the HGV E2 protein to CD81 was analysed by flow cytometry. Lymphocytes were stimulated with immobilized HGV E2, anti-CD81 or serum proteins from HGV-infected subjects and changes in CCR5 expression and CC chemokine secretion were determined.Results:We demonstrate that the HGV envelope protein E2 specifically binds to CD81 on T lymphocytes. This interaction induces a dose-dependent release of RANTES and down-regulation of CCR5 surface expression with concomitant intra-cellular accumulation of CCR5 proteins. This effect of HGV E2 on CCR5 expression was confirmed when lymphocytes were incubated with serum proteins from HGV-infected subjects. Finally, our cross-sectional analysis revealed CCR5 expression to be reduced by 53% and 36% on CD4 and CD8 lymphocytes of HGV-infected subjects, respectively (P <0.01).Conclusions:Our results demonstrate that an interaction of HGV E2 with CD81 leads to increased RANTES secretion and decreased CCR5 surface expression. This mechanism might contribute to the delayed progression of HIV-infection in HGV-coinfected patients.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:To demonstrate the use of HIV-1 reverse transcriptase (RT) recovered directly from plasma for phenotypic drug susceptibility testing.Methods:Plasma from HIV-1 infected individuals with and without drug resistance-associated mutations were selected for the study. The blind coded plasmas were treated to inactivate cellular enzymes. The virions were immobilized on a gel and washed to remove antiretroviral drugs and RT activity blocking antibodies. The immobilized virions were lysed; the viral RT eluted and quantified, all according to the ExaVir Load procedure. The drug sensitivity profiles of each RT were determined using serially diluted drugs and modified Cavidi HS Lenti RT kits.Results:The phenotypic drug sensitivity profiles of the RT and the patterns of drug resistance mutations were highly concordant. Plasma RT from virions devoid of mutations associated with drug resistance had average 50% inhibitory concentrations (IC50) of 1.5 ± 0.93 μM for nevirapine, 0.21 ± 0.099 μM for efavirenz, 7.1 ± 3.2 μM for delavirdine, 0.42 ± 0.15 μM for azidothymidine triphosphate and 0.059 ± 0.018 μM for didehydrothymidine triphosphate. The increase in IC50value for RT with drug resistance associated substitutions was from 3- to more than 65-fold for non-nucleoside inhibitors and between 2- and 30-fold for thymidine analogue drugs.Conclusion:RT derived from virions recovered from the plasma of HIV infected individuals can be used for analysis of phenotypic drug susceptibility. The methods presented provide rapid alternatives for analysing phenotypic drug susceptibility especially when the therapy is based on non-nucleoside RT inhibitors and thymidine-analogue drugs.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objective:In AIDS, early suppression of the viral load in the central nervous system is critical for the efficacy of antiretroviral therapy, in order to prevent the emergence of a reservoir of resistant strains of virus, and brain impairment in late stages of the infection. The blood–cerebrospinal fluid (CSF) interface (i.e. the choroidal epithelium) constitutes the most direct route to reach the ventricular meningeal and perivascular infected macrophages, and may modulate the cerebral biodisposition of antiretroviral drugs through various transport systems. Our aim was to address nucleoside drug transfer specifically across the blood–CSF interface, and identify the possible mechanisms involved in their transport.Methods:Drug influx and efflux were measured using anin vitrocellular model that reproduces the barrier and transport properties of the blood–CSF interfacein vivo. Transport mechanisms were investigated by competition studies.Results:The CSF influx rate of zidovudine was the highest, although moderate, followed by that of stavudine. The permeability coefficients of the other drugs tested were low. Zidovudine influx into the CSF is independent of thymidine transport systems, and more importantly is limited by an efflux mechanism. This efflux involves an apical (CSF-facing) carrier belonging to the solute carrier (Slc) 22 family of organic anion transporters, and can be inhibited by a therapeutic concentration of benzbromarone.Conclusions:The demonstration and characterization of this efflux mechanism is the basis for the development of specific inhibitory agents in view to increase the delivery of antiretroviral nucleoside analogs to the brain.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Objectives:To explore the effect of granulocyte macrophage colony stimulating factor (GM-CSF) on viral load and CD4 cell count during interruption of highly active antiretroviral therapy (HAART).Methods:Patients on effective HAART (CD4 cell count > 400 × 106/l; viral load < 50 HIV RNA copies/ml) were randomized to one of two groups: 12 weeks’ treatment interruption plus, during the first 4 weeks, 300 μg GM-CSF (Leucomax-Novartis) by subcutaneous injection three times weekly (GM-CSF group); 12 weeks’ scheduled treatment interruption (STI-only group). Viral load, CD4 cell count, clinical events and side effects of treatment were monitored.Results:Thirty-three patients, 15 in the GM-CSF group and 18 in the STI-only group, were evaluated according to the intention-to-treat principle. The two groups were well matched with regard to pre-HAART viral loads and CD4 cell counts. During STI, viraemia was approximately two to three times lower in the group receiving GM-CSF (max 4.97 versus 5.45 in STI-only group;P= 0.03). Fifteen out of 17 patients in the STI-only group showed a decrease in their CD4 cell count between weeks 0 and 4 (median decrease 231 × 106cells/l;P< 0.001); there was no such tendency in the GM-CSF group (P= non-significant when comparing CD4 cell counts at weeks 0 and 4). The median CD4 cell AUC (area under the curve) from week 0 to week 12 was higher in the GM-CSF group (9166 cells.week) than in patients without GM-CSF (7257),P= 0.02. GM-CSF produced local reactions in 88% of patients, and generalized symptoms such as fever, back pain or headache in 82% of patients. Seventy-six percent of patients completed the planned course of 12 injections.Conclusions:The administration of GM-CSF blunted the viral rebound following interruption of HAART, and largely prevented a decrease of CD4 cell counts during a 12-weeks-treatment interruption. A better understanding of the underlying mechanism(s) may help to identify synergistic treatment targets and improved administration protocols to enhance control of chronic HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Background:To assess the postnatal transmission (PT) risk of HIV-1 after a maternal short-course zidovudine regimen in a breastfeeding population.Methods:Data were pooled from two trials: ANRS 049a DITRAME (Abidjan, Côte d'Ivoire and Bobo-Dioulasso, Burkina-Faso) and RETROCI (Abidjan). Consenting HIV-1 seropositive women were randomized at 36–38 weeks’ gestation between September 1995 and February 1998, to receive oral zidovudine or placebo: one tablet twice daily until delivery, and in DITRAME only, for 7 more days. A PT case was infection in a child with a negative HIV-1 PCR at age ⩾ 30 days who later became infected as defined by a positive HIV-1 PCR, or if aged ⩾ 15 months, a positive HIV serology. Cumulative risks (CR) of PT were computed using a competing risk approach with weaning as a competing event.Findings:At age 24 months, CR for PT were similar in the zidovudine (9.8%, n = 254) and placebo groups (9.1%, n = 225). In a multivariate model of PT risk factors, the treatment effect was not significant, maternal CD4 cell count < 500 × 106/l at entry tripled the hazard compared to women with CD4 cell counts ⩾ 500 × 106/l [hazard ratio (HR), 3.14; 95% confidence interval (CI), 1.31–7.49] as well as an increased maternal plasma viral load at entry (HR, 2.65 for 1 log10increase; CI, 1.75–4.00).Interpretation:PT occurred at a similar rate between arms and therefore reduced the long-term overall efficacy of this peripartum zidovudine regimen at age 24 months. The higher risk of PT among women with low CD4 cell count emphasizes the importance of identifying interventions to prevent PT for these women.

ISSN:0269-9370    

出版商:OVID    

年代:2003

数据来源: OVID