ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo examine the B-cell stimulatory properties of the regulatory Nef protein of HIV-1.MethodsThe effect of the HIV-1 regulatory proteins Nef, Tat and Vif, were analyzed for their ability to induce differentiation of normal B lymphocytes into immunoglobulin secreting cells (ISC).ResultsA recombinant Nef protein, but neither Tat or Vif, was able to induce ISC in peripheral blood lymphocyte (PBL) cultures of HIV-1-seronegative donors. Another recombinant Nef protein, d-Nef, with a truncated amino terminal (deletion of 34 amino acids) failed to induce B-cell differentiation. Pretreatment of the Nef protein with a polyclonal anti-Nef-antibody abrogated its B-cell stimulatory activity. The Nef-induced B-cell differentiation was dependent on cell-to-cell contact. Cell surface molecules leukocyte function-associated molecule (LFA)-1, intracellular adhesion molecule (ICAM)-1, human lymphocyte antigen-DR and B7 were involved in the T-B-cell interaction because monoclonal antibodies to these molecules abrogated the Nef-induced B-cell differentiation response. The Nef protein was able to induce interleukin (IL)-6 messenger (m)RNA and IL-6 protein secretion in PBL, with monocytes as the primary source.ConclusionsThese findings indicate that regulatory (Nef) proteins of HIV-1 contribute to the intense B-cell activation that occurs in association with HIV-1 infection. T-B-cell contact-dependent interaction and induction of IL-6 by these proteins appear to play major roles in this process.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo determine the serum levels of the soluble form of the CD30 (sCD30) activation molecule in the early phase of HIV-1 infection, and to investigate the possible correlation with evolution to AIDS.MethodssCD30 values were determined by an enzyme-linked immunosorbent assay (ELISA) on serum samples collected at the time of the first evidence of HIV-1 infection in 110 individuals with a median follow-up of 56 months (range, 12–88 months), at the A1 (74 cases) or A2 (36 cases) stages of the 1993 revised Centers for Disease Control and Prevention classification. The data were evaluated using established clinical and immunological parameters, including circulating CD4+ T-cell count. The controls were 110 blood donors and 51 HIV-1 -negative subjects belonging to groups at risk for HIV-1 infection.ResultsElevated sCD30 levels ( 20 U/ml) were found in 83.6% of HIV-1 -infected cases and in 47% of at-risk seronegatives. Data analysis revealed that HIV-1-infected patients with higher sCD30 levels (>35 U/ml) experienced faster disease progression (P= 0.0002). This was also the case in patients at the earliest stage (A1) of HIV infection (P= 0.0027). In these latter cases the predictive value of sCD30 was independent of the initial absolute number of circulating CD4+lymphocytes.ConclusionsSerum levels of sCD30 are increased in the large majority of patients in the early phase of HIV-1 infection and represent an indicator of progression to AIDS independent of other prognostic parameters.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectivesSince human liver endothelial cells allow HIV-1 multiplicationin vitro, we investigated whether HIV induced functional alterations in these cells in primary culture.DesignDirect evidence of the replication of HIV in endothelial cells is sparse, but clotting abnormalities and thrombi, which suggest the existence of an endothelial dysfunction, have been observed in HIV-infected patients. We therefore studied the storage and release of endothelial-specific factors in primary cultures of liver endothelial cells infected with HIV, as well as their cytoskeleton, pinocytic and phagocytic properties.MethodsIntracellular storage of von Willebrand's factor (vWF) was determined by immunofluorescence and computer image analysis. Excretion of vWF, protein S and endothelin-1 was measured using an enzyme-linked immunosorbent assay and radioimmunoassay. Cytoskeletal constituents were studied by light microscopy. The pinocytosis of acetylated low-density lipoproteins and the phagocytosis of latex beads were analysed under light and electron microscopy.ResultsThe synthesis of vWF is markedly decreased in HIV-infected liver endothelial cells, as is the excretion of endothelin-1. In contrast, the excretion of protein S remains unaffected and the cytoskeletal network appears to be unaltered. Pinocytosis and phagocytosis are preserved.ConclusionsHIV infection triggers non-lethal functional alterations in cultured human liver sinusoidal endothelial cells, with a selective impairment in the storage and/or the excretion of endothelial-specific factors such as vWF. This functional modulation could play a role in the pathophysiology of HIV-induced disease.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo determine thein vitrosusceptibility of primary clinical isolates and laboratory strains of HIV-1 to XM323.MethodsThe AIDS Clinical Trials Group/US Department of Defense p24 antigen-based consensus assay was used to determinein vitrosusceptibility of 57 primary clinical isolates and three laboratory strains of HIV-1 to XM323, zidovudine, zalcitabine (ddC), and didanosine (ddl).ResultsThe concentrations of compound required to inhibit viral p24 antigen production by 50% [median inhibitory concentration (IC50)] for nucleosides were as follows: zidovudine, 0.001->5μM; ddC, < 0.01–0.23μM; ddl, 0.2-25μM). Against both nucleoside susceptible and resistant isolates XM323 exhibited potent inhibition with IC50values of < 0.02–0.27 μM and IC90values of 0.03–1.17 μM.ConclusionsXM323 is a potent inhibitor of diverse clinical isolates of HIV-1in vitroand represents a novel class of non-peptidyl inhibitors of HIV-1 protease.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo study the TH1->TH2 cytokine switch, thought to occur during the progression of HIV infection.DesignWe investigated interleukin (IL)-2, interferon (IFN)-γ, IL-4, IL-6 and IL-10 production by phytohaemagglutinin (PHA)-stimulated and unstimulated peripheral blood mononuclear cell (PBMC) cultures from HIV-negative controls and HIV-positive subjects, stratified according to the Centers for Disease Control and Prevention (CDC) criteria. We correlated the above parameters with markers of disease progression.MethodsCytokine production was measured in supernatants using enzyme-linked immunosorbent assay (ELISA) in 40 patients and 17 controls. To evaluate disease progression, we also determined CD4+ cell counts, PHA-induced proliferative response, p24 release and spontaneous immunoglobulin (Ig) G and IgM production.ResultsIn agreement with the TH1->TH2 switch hypothesis, we found that in the course of HIV disease mitogen-stimulated IL-2 production decreased, spontaneous and stimulated IL-6 production and spontaneous IL-10 secretion increased; IL-4 showed an increasing trend, although it was reduced in HIV-positive subjects. Finally, immunoglobulin production increased over time. In contrast, mitogen-stimulated IFN-γ and IL-10 production did not change among the CDC categories, although the former decreased and the latter increased in comparison with HIV-negative controls.ConclusionsOur data partially agree with the TH1->TH2 switch hypothesis. Since IL-6 and IL-10 are produced by different cell types, whose proportions and functional features vary in the course of the disease, further experiments with purified lymphocyte subsets and monocytes are required. Nevertheless, as already suggested, we believe that a switch from a type 1 to a type 2 response occurs in HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo determine the relationships betweenin vivozidovudine (ZDV) phosphorylation in cells from HIV-infected patients and markers associated with disease progression and drug toxicity.DesignA pharmacokinetic study of ZDV metabolism sponsored by the AIDS Clinical Trials Group (protocol 161). Plasma and intracellular pharmacokinetics following a 100 mg oral dose of ZDV were determined at weeks 4 and 24 of initial therapy in adult patients. Plasma concentrations and phosphorylated ZDV were determined by radioimmunoassay, and area under the concentration-time curves (AUC) were compared with clinical data collected during the pharmacokinetic study.SettingAn outpatient setting at the University of Cincinnati AIDS Treatment Center, Cincinnati, Ohio, USA.PatientsHIV-infected adults with CD4+ lymphocyte counts 200–500 × 106cells/I with no prior history of anti-HIV therapy and no active infections requiring systemic therapy. Of 30 patients enrolled, 21 were evaluable.InterventionsNone.Main outcome measuresAUC of plasma ZDV and intracellular total phosphorylated ZDV were compared with change from baseline of the following surrogate markers: CD4+ lymphocyte count, %CD4+ lymphocytes, CD4+/CD8+ cell ratio, serum β2-microglobulin, serum neopterin, neutrophils, red cell count, and hemoglobin.ResultsNo correlations between plasma AUC and markers of therapeutic response were observed. However, significant positive correlations were observed between the AUC of total phosphorylated ZDV and changes in the %CD4+ lymphocytes and CD4+/CD8+ lymphocyte ratio; a negative correlation was observed with change in hemoglobin. Patients who responded to ZDV therapy, as measured by these variables, demonstrated significantly higher intracellular AUC (>3 pmol × h/106cells) than those who did not (approximately 2 pmol × h/106cells).ConclusionsThe ability of HIV-infected patients to phosphorylate ZDV correlates with changes in markers associated with drug effect and toxicity. Potential individualization of therapy through monitoring of total phosphorylated ZDV in patients therefore warrants further exploration.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo study the influence of HIV infection on phagocyte function. To date, the results of phagocyte function studies in HIV-infected patients have been contradictory. This is the first longitudinal study of these functions in HIV infection.DesignWe followed 50 individuals with HIV infection for 2–51 months (mean, 28 months) and examined polymorphonuclear leukocyte (PMNL) and monocyte functions at intervals of 0.5–1 years.MethodsPMNL random migration and chemotaxis were assessed using an under-agarose method, and PMNL and monocyte oxidative metabolism by chemiluminescence production during phagocytosis of opsonized zymosan.ResultsPMNL random migration and chemotaxis were impaired at entry into the study by 15 and 19%, respectively. After 3 years the reduction was 35 and 32%, respectively. The mean chemiluminescence production by PMNL was reduced by 6% at entry into the study. After 4 years a decrease of 18% was observed. The decrease in PMNL function was most marked in patients with lymphadenopathy syndrome or AIDS. No significant change in monocyte chemiluminescence production was detected at any time during the study.ConclusionsA distinct and progressive decrease of PMNL function occurs during HIV infection. This may contribute to increased susceptibility to opportunistic infections in HIV-infected patients. For monocytes, chemiluminescence production is not influenced by HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectiveTo determine the effect of HIV-1 infection on immunoglobulin (Ig) G and IgA antibody response and circulating antibody forming cell response to oral immunization with the B subunit of cholera toxin.DesignHealthy UK volunteers, and HIV-1-positive UK and Kenyan volunteers at different clinical stages of HIV-1 infection received two oral immunizations. CD4+ T cells, serum β2-microglobulin and neopterin were measured as surrogate markers of disease stage, and correlated with immunization response.MethodsSerum antitoxin IgG and IgA measured by enzyme-linked immunosorbent assay and antitoxin IgG, IgA and IgM antibody-forming cells detected by enzyme-linked immunospot assay at different times after two oral immunizations.ResultsUK HIV-positive volunteers (mean CD4+ T cell count, 52 × 106/l) responded poorly to primary and booster immunization. HIV-infected Kenyans (752 × 106/l CD4+ T cells) had a significant primary and booster antibody response, whereas those with a mean CD4+ T cell count 186 × 106/l had an insignificant primary, but significant booster response. Two oral immunizations induced antibody responses in HIV-positive Kenyan groups (who may have prior immunity from exposure to environmental bacterial toxins) of similar or greater magnitude to healthy UK volunteers.ConclusionsMucosal immunization may recall immune memory and be of benefit in early and moderately advanced clinical HIV disease. The findings have important clinical implications in that mucosally targeted vaccines are potentially useful in this group of patients.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID

摘要:

ObjectivesTo report the occurrence of HIV-related mucosal candidosis that fails to respond to fluconazole, to establish the correlation betweenin vitrosusceptibility testing and clinical failure, and to assess the efficacy of alternative treatments.DesignChart review of all patients with fluconazole failure and all patients with CD4 counts < 50 × 106/l continuing to respond to fluconazole, and prospectivein vitrosusceptibility testing ofCandida.SettingA regional treatment centre for HIV-infected individuals in north-west England.PatientsA cohort of 155 HIV-positive individuals with CD4 counts < 300 × 106/l cells.Main outcome measuresClinical fluconazole failure was defined as symptomatic oropharyngeal or oesophageal candidosis despite fluconazole ≥ 100 mg per day for 10 days.In vitrosusceptibility to fluconazole was determined forCandidaisolates. Cumulative 12-month fluconazole dose and time from first fluconazole therapy and prophylaxis were recorded.ResultsNine (5.8%) patients meeting the definition of fluconazole failure were identified.In vitrosusceptibility to fluconazole of temporally related oropharyngeal isolates was reduced in all cases. Intravenous amphotericin B was the only effective treatment for these patients when symptoms were severe suggesting azole cross-resistance. One patient, who had received alternative treatments for 9 months, reverted fromin vitroand clinical fluconazole sensitivity but relapsed within 6 weeks of resuming fluconazole. The median fluconazole dose over the preceding 12 months for the eight adult cases was 386 mg weekly. The median dose for the same period was 79 mg weekly in 28 patients with CD4 counts < 50 × 106/l but without fluconazole failure (difference, 307; 95% confidence interval, 199–514;P< 0.0001).ConclusionA substantial problem of clinical fluconazole failure has developed among HIV-positive patients who have recurrent problematic mucosal candidosis.

ISSN:0269-9370    

出版商:OVID    

年代:1994

数据来源: OVID