摘要:

Objectives and designMeasurement of phosphorylated zidovudine (ZDV) inside infected cells is more likely to provide satisfactory dose response relationships than serum concentrations. This study provides information on ZDV phosphorylation in HIV-seronegative volunteers (n = 5) and in patients with HIV infection (n = 12).Methods:Intracellular ZDV phosphate metabolites were measured in peripheral blood mononuclear cells isolated from whole blood by density cushion centrifugation. Cells were washed and extracted overnight with 60% methanol prior to analysis by high performance liquid chromatography. Fractions eluted from the column corresponding to ZDV, ZDV monophosphate (ZDV-MP), ZDV diphosphate (ZDV-DP) and ZDV triphosphate (ZDV-TP) were collected, hydrolysed by acid phosphatase and ZDV levels quantified by radioimmunoassay.Results:The area under the plasma ZDV concentration-time curve (AUC06–6h) was similar in seronegative volunteers and patients [mean ± SD, 4.64 ±2.50 versus 5.56±2.67 μmoles/l h; 95% confidence interval (Cl, −4.39–2.23;P=0.646, Mann-Whitney U test]. However, ZDV phosphorylation was greater in patients, with the AUC0–6hfor total phosphate metabolites being 5.91 ±3.42 pmoles/106cells h compared with seronegative volunteers (0.66±0.48 pmoles/106cells h; 95% Cl, −8.35 to –2.32;P= 0.0003). The concentration of ZDV-TP was similar in both groups, the increase in total phosphates in patients being due primarily to ZDV-MP. ZDV-MP AUC0–6hand total ZDV phosphate AUC0–6hwere closely correlated (r2= 0.94). The relationship between total ZDV phosphate AUC0–6hand the CD4 count demonstrates that patients with a count < 100×106/l have much higher ZDV phosphate levels, predominantly ZDV-MP.Conclusion:ZDV is phosphorylated to a greater extent in patients than in healthy volunteers. The increased ZDV-MP in patients with low CD4 counts may explain the well known occurrence of increased ZDV toxicity in patients with more advanced disease. The ability to measure ZDV phosphorylated metabolites (without the administration of radiolabelled nucleoside) represents a significant advance in our understanding of the clinical pharmacology of the drug.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Objective:Neurologic complications are common in patients with AIDS. Herpes zoster is a common early manifestation of HIV infection, but there have been few reports of encephalitic complications and nearly all have been postmortem. We report four cases of varicella zoster virus (VZV) meningoencephalitis diagnosed and treated antemortem, and briefly review the relevant literature.Setting:Mount Zion Medical Center, San Francisco, California, USA.Patients:Four HIV-positive male patients with antibodies to VZV in their cerebrospinal fluid.Intervention:Treatment with intravenous acyclovir (three cases) and intravenous ganciclovir (one case), which resulted in resolution of all symptoms except blindness in one patient.Conclusion:Antibodies to VZV in the cerebrospinal fluid of HIV-positive individuals may allow early diagnosis and lifesaving treatment of VZV meningoencephalitis.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Objectives:To study the biological properties of the immunosuppressive peptide (ISU-peptide) of HIV-1, a 17-mer corresponding to the amino-acid domain 583–599 of the transmembrane glycoprotein gp41 of HIV-1. This peptide exhibits sequence homology to the highly conserved ISU-peptide of type C and D retroviruses. Also, to study the immune response against the corresponding gp41 epitope in AIDS patients.Design:The ISU-peptide and control peptides were synthesized and tested for immunosuppressive activity in differentin vitrolymphocyte proliferation assays. Antibody responses were tested using a peptide enzyme-linked immunosorbent assay. A new property of the ISU-peptide, inhibition of HIV-1 replication, was investigated using a cytopathogenicity assay.Results:The ISU-peptide of HIV-1 and the immunosuppressive peptides of type C and type D retroviruses possess similar functional properties. They inhibit mitogen-induced and lymphokine-dependent T-lymphocyte proliferation, they are interspecies-reactive, they must be conjugated to a carrier protein in order to be immunosuppressive, and their N-terminal octamers represent the minimal immunosuppressive domain. HIV-infected individuals develop antibodies against an epitope located at the C-terminal end of the ISU-peptide and the number of responders and antibody titres decrease during progression to AIDS. In addition to its immunosuppressive activity, the ISU-peptide of HIV-1 inhibits the cytopathic effect of HIV-1 on human MT4 cells, suggesting interference with virus replication.Conclusions:The immunosuppressive property of the ISU-peptide suggests that gp41 might contribute to the development of AIDS. The evolutionary conservation of the immunosuppressive domain and the ability of the corresponding ISU-peptide to inhibit HIV replication suggest that this domain plays an important role in the life cycle of HIV-1.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Objectives:(1) To determine the safety and feasibility of repetitive reinfusions of activated autologous CD8 cells followed by low-dose continuous interleukin (IL)-2 infusion in patients with AIDS. (2) To study the relationships between clinical responses, surface marker phenotypic distributions and cytokine expression patterns of both cultured CD8 cells and lymphocytes in the peripheral blood compartment.Design:Six adult patients with Centers for Disease Control and Prevention group IV HIV-1 disease ranging from mild to severe, were studied. All patients were receiving zidovudine prior to and during the study period, and had initial CD4 and CD8 cell counts >50 and 200×106/l, respectively.Methods:Autologous CD8 T cells (108-1010) were reinfused five times afterex vivoculture and stimulation with phytohemagglutinin and recombinant (r) IL-2. The fifth such infusion was followed by 5 days of rlL-2 infusion. Phenotypes and cytokine expression patterns of the expanded cells were determined as well as serum levels of immune mediators throughout the study.Results:Patients showed stable CD4 and CD8 cell counts, p24 antigenemia, and minimal toxicity over the 24-week protocol study. Clinical improvement was observed in lymphadenopathy (six out of six), oral hairy leukoplakia (three out of four), and Kaposi's sarcoma (KS; two out of two) in the patients studied. In vivo induction of detectable levels of bioactive acid-stable interferon (IFN)-a, but not of other cytokines studied, upon activated CD8 cell reinfusion was associated consistently with improvement of oral hairy leukoplakia. However, partial regression of KS was observed after the CD8 cell infusion cycles and without IFN-α induction. In one of the two patients studied, KS regression was associated with decreased IL-1 α serum levels. In the other patient, who had failed previous IFN-α therapy, KS regression was observed after a decline in reinfused CD8 cell-associated gene expression of tumor necrosis factor (TNF)-β. Both IL-1 α and TNF-β are growth factors for KS cells.Conclusions:These observations demonstrate the feasibility and safety ofex vivoCD8 cell activation, expansion, and reinfusion, and rlL-2 infusion in AIDS patients. The findings in this Phase I trial suggest potential clinical efficacy and encourage Phase II trials. The correlations obtained between clinical and immunological states could contribute to an understanding of the relationship between CD8 T-cell function and HIV-1-associated disease progression.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Objective:To compare the viral burden and the biological phenotype of HIV-1 isolates obtained from lymphoid node mononuclear cells (LNMC) and peripheral blood mononuclear cells (PBMC) in 11 HIV-infected patients.Methods:Viral burden was quantified by cocultivating LNMC and PBMC from HIV-infected patients with PBMC from seronegative donors. For each patient, LNMC and PBMC isolates were characterized in terms of susceptibility to neutralizing antibodies, syncytium-inducing capacity and sensitivity to zidovudine.Results:Our data show that: (1) viral burden was 1.73 log higher in LNMC than PBMC in patients with persistent generalized lymphadenopathy and only 0.37 log higher in patients with AIDS-related complex; (2) five out of 11 LNMC bulk isolates were phenotypically distinct from autologous PBMC isolates; (3) in three patients, the autologous serum neutralized the PBMC isolates but not the LNMC isolates.Conclusions:These results suggest that the relatively high level of HIV-1 replication in lymph nodes may favour the emergence of viruses exhibiting specific phenotypes, including neutralization escape variants. The existence of viral variants in lymphoid tissue at all stages of HIV infection may elucidate certain aspects of the pathogenesis of HIV-1 infection.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Objectives:To determine the neutralizing antibody patterns to HIV-1ANT70(ANT70) and HIV-1IIIB(IIIB) in human sera obtained from HIV-1-infected individuals from different African countries and Belgium. Second, to correlate the presence of neutralizing antibodies in sera and their ability to bind to synthetic peptides derived from eight different HIV-1 V3 loop sequences.Design and methods:Forty sera from Belgium and 88 obtained from seven countries in Africa were tested for their ability to neutralize ANT70 (one of the most genetically divergent HIV-1 isolates documented), and IIIB. Sera found to cross-neutralize both viruses were further challenged with four HIV-1 field isolates. All sera were tested on a panel of V3 loop peptides obtained from different HIV-1 genotypes.Results:Four patterns of sera were identified, including 33 (26%) sera not neutralizing any of the isolates, seven (5%) sera neutralizing only ANT70, 45 (35%) sera neutralizing only 1MB, and 43 (34%) sera cross-neutralizing both isolates. Sera capable of cross-neutralizing both ANT70 and IIIB consistently neutralized other field isolates tested, with a remarkable similarity in neutralizing antibody titre. A significantly higher number of sera cross-neutralizing both ANT70 and IIIB compared with sera lacking neutralizing antibodies, reacted simultaneously in enzyme-linked immunosorbent assays (ELISA) with three or more V3 loop peptides belonging to HIV-1 strains of different genotypes. However, none of the sera cross-neutralizing ANT70 and IIIB were reactive in ELISA with the ANT70 V3 loop peptide.Conclusion:These results suggest that despite pronounced genomic variation of the HIV-1ANT70isolate, there are strongly conserved neutralizing epitopes situated outside the V3 loop that are shared by other HIV-1 isolates. These findings suggest that genetic variation might be surmountable in the design of a polyvalent HIV vaccine, if neutralizing antibodies are found to be correlates of protection in HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Objectives:B-cell hyperactivity and hypergammaglobulinaemia with high levels of HIV-1-specific antibody occur during HIV-1 infection. We investigated the role played by antigen-presenting cells (APC) in the ongoing production of antibody.Methods:Adherent monocytes and non-adherent low density dendritic cells were enriched from peripheral blood of patients at different stages of HIV-1 infection (Centers for Disease Control and Prevention categories II, III and IV) and from control subjects at high or low risk of HIV infection. Different concentrations of lymphocytes were cultured in 20 ml hanging drops in the presence or absence of autologous dendritic cells or monocytes. Antibodies to p24 and gp120 were assessed by enzyme-linked immunosorbent assay.Results:Lymphocytes taken from asymptomatic HIV-1-seropositive subjects and depleted of APC produced low or moderate levels of antibody to gp120 or p24in vitro. However, adding back autologous dendritic cells significantly enhanced antibody production, although fewer samples showed responses to p24 than to gp120. Less antibody production was stimulated using cells from patients with persistent generalized lymphadenopathy, or if monocytes rather than dendritic cells were added back. Little or no antibody was produced by cells from patients with AIDS and no antibody was detected in cultures of cells from seronegative individuals with low or high risk for infection.Conclusions:The evidence suggests that ongoing humoral responses to HIV-1 are fuelled by dendritic cells. Thus, the dominance of humoral over cell-mediated responses in HIV-1 infection may depend upon signalling via dendritic cells. Changes in signalling by dendritic cells could be central to the immunologic features of HIV-1 infection.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

Objective:To evaluate the effectiveness of supervised therapy for tuberculosis (TB) in patients with HIV infection.Design:Retrospective, chart review.Patients:Patients with TB and HIV infection. Setting: Urban, public TB clinic.Main measures and results:A total of 107 patients with TB and HIV infection were studied. Most were men (78%), African American (91%), uninsured or on Medicaid (88%), and 67% were injecting drug users. TB was diagnosed before AIDS in 31% of subjects, at the time of AIDS in 32%, and after AIDS in 37%. Clinical features varied by stage of HIV disease. Sixteen patients received no therapy and died before TB was diagnosed, 10 died during the first 8 weeks of treatment. Seventy-eight patients received > 8 weeks therapy, of whom 48 (62%) were given directly observed therapy twice weekly and 30 (38%) received self-administered daily therapy. Patients who received directly observed therapy were more likely to complete 6 months of therapy (96 versus 76%,P=0.02) and more likely to survive after therapy ended (85 versus 57%,P=0.01). By logistic regression, directly observed therapy, AIDS diagnosed before TB, and age were significantly associated with survival outcome.Conclusion:Directly observed therapy for TB in patients with HIV infection is highly effective and associated with better adherence to therapy and survival.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID