摘要:

ObjectiveMice with severe combined immunodeficiency (SCID) transplanted with human peripheral blood lymphocytes (hu-PBL) have been shown to be useful as an animal model for HIV-1 infection. This model was used to assess the ability of a human anti-gp120 antibody to protect against HIV-1 infection.Design and methodshu-PBL-SCID mice were injected with an HIV-1 broadly neutralizing human monoclonal antibody against the gp120 CD4-binding site prior to challenge with HIV-1SF2. The antibody b12, employed for these studies, was isolated from an antibody phage-display library prepared from bone-marrow of a long-term asymptomatic HIV-1-seropositive donor. Both Fab fragments and whole immunoglobulin (Ig) G1 b12 antibody were assessed for protection.ResultsFab b12, tested at a dose ≈1.9mg/kg, was able to protect 25% of hu-PBL-SCID mice from HIV-1 infection. IgG1 b12, which displayed favorable pharmacokinetic properties, showed a dose-dependent protection that was complete with a regimen of two injections of 100 μg per mouse. Thein vivoprotective dose of antibody at the time of virus challenge was estimated to be 4.5–7 mg/kg from antibody clearance data.ConclusionsThis study demonstrates for the first time that complete protection against HIV-1 infection can be achieved in the hu-PBL-SCID model by passive immunization with physiologically relevant doses of a human gp120 CD4-binding site antibody derived from natural infection.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo study the Vβ T-cell repertoire in peripheral blood lymphocytes (PBL) during acute HIV syndrome by using several anti-Vβ monoclonal antibodies (MAb) and to analyse its functionality by stimulating PBL with superantigens (SAg) such asStaphylococcus aureusenterotoxins.MethodsCytofluorimetric analysis of Vβ T-cell-receptor expression was performed on PBL from eight patients with symptomatic, acute HIV-1 primary infection, showing a dramatic decrease of CD4+ PBL accompanied by a marked increase in activated/memory CD8+ T cells, and on 12 age- and sex-matched healthy controls. PBL were then isolated, stimulated with different SAg, anti-CD3 MAb or phytohaemagglutinin and cultured for 3 days. PBL capability to progress through cell cycle was studied by the classic cytofluorimetric method of bromodeoxyuridine incorporation and DNA staining with propidium iodide.ResultsDespite the presence of a few expansions of some Vβ families among CD8+ T lymphocytes, no gross alterations in T-cell repertoire were present in patients with acute HIV syndrome. Its functionality was maintained overall, as PBL responsiveness to SAg was well preserved. Interestingly, all CD8+ T cells, although bearing different Vβ T-cell receptors, expressed marked signs of activation, i.e., CD45RO, CD38 and major histocompatibility complex class II molecules, and also high amounts of CD11a and CD18.ConclusionsOur data suggest, at least in the early phases and in the acute form of the infection, that HIV is not likely to act as a SAg. However, further studies are needed to analyse other sites, such as lymph nodes, where HIV could exert other, significant effects, and to study the expression of other Vβ families than those investigated here.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectivesTo characterize HIV-specific cytotoxic T-lymphocyte (CTL) activities in HIV-2-infected individuals and to relate these to HIV-2 proviral load.MethodsPeripheral blood mononuclear cells were collected from 16 HIV-2-seropositive and four HIV-1/-2 dually seropositive subjects. CTL were restimulated with autologous phytohaemagglutinin-stimulated blasts and CTL activities in 'bulk' cultures were evaluated 7 and 14 days later by a standard51Cr-release assay using autologous B-cell lines infected with recombinant vaccinia expressing HIV-2 Gag, Pol or Nef protein. Proviral load was quantified by polymerase chain reaction (PCR) which used HIV-2 long terminal repeat primers and an external standard control made by an HIV-2CBL-22chronically infected C8166 cell line. A biotinylated primer was used to capture the35S dATP-incorporated secondary PCR product in a quantitative radiometric assay.ResultsAfter 14 days of culture CTL responses against Gag or Pol protein were seen in 18 (90.0%) and 14 (70.0%) out of 20 subjects, respectively, whereas a CTL response was noted against Nef protein in five (25.0%) out of 20 subjects. In 14 (70.0%) out of 20 subjects multiple HIV proteins were simultaneously recognized. The sum of specific lysis (%) against HIV-2 Gag, Pol and Nef at 30:1 effector-to-target ratio, or specific lysis of the dominant CTL response, correlated strongly with HIV-2 proviral load expressed as copies per 105CD4+ cells (r=-0.625, P=0.003 and r=-0.674,P= 0.001, respectively).ConclusionHIV-2-specific CTL to multiple gene products was demonstrated in most HIV-2-infected individuals. An inverse correlation between the level of CTL activity and proviral load was found, which supports the hypothesis that CTL are important in the control of HIV-2 replication.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo analyse changes in T-lymphocyte subsets in patients with primary HIV infection and to determine their specificity (and therefore their diagnostic utility) by comparing these changes with those seen in other acute illnesses as well as in HIV-uninfected patients.MethodsT-lymphocyte subsets were analysed by two- and three-colour flow cytometry, and compared between HIV seroconverters (n = 16), HIV-infected (n = 18) and uninfected (n = 33) controls, patients with infectious mononucleosis (n = 7), and patients suspected clinically of having primary HIV infection but who were later found to be uninfected (referred to as HIV non-converters; n = 17).ResultsCD4+ lymphocyte counts were significantly lower in HIV seroconverters (mean, 444×106/I) than in the HIV non-converters (793×106/I;P= 0.003), HIV-seronegative controls (888×106/I;P< 0.0001) and, to a lesser extent, those with mononucleosis (694 × 106/I;P= 0.045). The reduction in CD4+ lymphocytes occurred in both the CD45RA+ (55%) and CD45RO+ (33%) subsets. CD8+ lymphocyte counts were significantly higher in HIV seroconverters (942×106/I) than in HIV non-converters (570×106/I;P= 0.003) and seronegative controls (467×106/I;P< 0.0001), but significantly lower than in the mononucleosis group (3682×106/I;P= 0.004). The CD8+ cells in the HIV seroconverters had increased coexpression of CD45RO, human leukocyte antigen (HLA)-DR, CD38 and CD11a/CD18. The mean CD4:CD8 ratio in the HIV seroconverters was 0.49, versus 1.52 in the non-converters (P< 0.0001), 2.08 in the seronegative patients (P< 0.0001) and 0.37 in the mononucleosis patients (P> 0.2).ConclusionsPrimary HIV infection is characterized by a depletion of CD4+ lymphocytes, especially of the CD45RA+ phenotype, and by an increase in CD8+ lymphocytes with an activated phenotype; the latter was also seen in patients with infectious mononucleosis but not in HIV non-converters or HIV-seronegative patients. Patients suspected clinically of having primary HIV infection but with normal T-cell phenotype are less likely to have primary HIV infection. These phenotypic changes, as well as an inverted CD4: CD8 ratio, can readily distinguish patients with primary HIV infection from HIV-uninfected patients except those with infectious mononucleosis. Therefore, T-cell-subset enumeration may be useful in the diagnosis of primary HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Objective and designIn this study we used synthetic peptides corresponding to the third variable region (V3) in the envelope protein gp120 of 14 different HIV-1 strains, and tested whether V3-specific T-cell responses are HIV-1 strain-specific or broadly cross-reactive in nine chimpanzees chronically infected with HIV-1 mIIIB.MethodsPeripheral blood mononuclear cells isolated from nine HIV-infected chimpanzees and two uninfected controls were tested, by the [3H]-thymidine incorporation assay, for proliferative responses against phytohemagglutinin, control peptide and V3-loop peptides corresponding to 14 different HIV-1 strains. Serum samples collected from the chimpanzees were analyzed by enzyme-linked immunosorbent assay for antibodies against the V3 peptides.ResultsChimpanzees 100, 139 and 175 exhibited high level of proliferative response directed against the cognate V3 peptide from HIV-1IIIBand also showed cross-reactivity to V3 peptides from 13, seven and 13 of 13 other HIV-1 strains, respectively. Additionally, five out of nine chimpanzees showed cross-reactive proliferative responses to V3 peptides from at least eight different HIV-1 strains, while significant proliferation to V3 peptides from two or more HIV-1 strains was observed in seven out of nine chimpanzees. On the other hand, four out of nine chimpanzees showed antibody response directed against the cognate V3 peptide from HIV-1IIIB, and serum from only one chimpanzee (100) showed cross-reactive antibody to six different V3 peptides.ConclusionsOverall, these studies in chimpanzees chronically infected with HIV-1IIIBindicate that with respect to the immunodominant V3 region, the virus-induced T-cell immunity is directed against a broad spectrum of HIV-1 strains.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo establish whether an outpatient, 2-day oral desensitization protocol would be both safe and effective in HIV-infected patients with previous trimethoprimsulfamethoxazole (TMP-SMX) intolerance.DesignA single center trial of TMP-SMX desensitization in HIV-infected patients with prior TMP—SMX hypersensitivity reactions.MethodsHIV-infected patients with CD4 lymphocyte counts < 250×106/I cells or CD4% < 20% with previous non-life-threatening hypersensitivity reactions to TMP-SMX were eligible. The desensitization protocol utilized 40 graduated doses over 36 h; the first 28 doses (7.5 h) of the protocol were given in an outpatient clinic with the remaining doses taken at home.ResultsTwenty-seven (60%) of the 45 subjects completed the protocol and were subsequently maintained on daily TMP-SMX without adverse reactions (mean follow-up, 9 months; range, 4–16 months). Patients with CD4 counts < 100×106/I cells were just as likely as patients with higher CD4 counts to tolerate the desensitization. No patient required hospitalization for treatment of an adverse reaction.ConclusionOral desensitization to TMP-SMX in HIV-infected patients is a useful option in the management of patients with advanced HIV disease and prior intolerance to TMP-SMX.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectivesTo assess the temporal trends in incidence of tuberculosis (TB) in HIV-infected patients, to evaluate the impact of pulmonary TB on the Centers for Disease Control and Prevention (CDC) 1993 AIDS case definition and to assess the frequency ofMycobacterium tuberculosisstrain resistance.DesignA retrospective study within a cohort.SettingThe Bordeaux University Hospital and three general hospitals in Aquitaine, southwest France.SubjectsSince 1985, HIV-infected in- and outpatients aged >13 years have been included in the Aquitaine cohort. Reported cases of pulmonary and extrapulmonary TB were investigated and records cross-referenced with the files of the TB reference laboratory.ResultsAs of 30 June 1993, the Aquitaine cohort (3119 patients) accounted for 6409 person-years (PY) of follow-up. TB was diagnosed in 139 patients (average annual incidence, 2.17 per 100 PY) of whom 79 had bacteriological diagnosis, 13 histological diagnosis and 47 clinical and/or radiological diagnosis. Extrapulmonary TB accounted for 40% of the cases. Intravenous drug use was more frequent in the group who developed TB (50%) than in the rest of the cohort (40%) (P= 0.009). There was an increase in the incidence rate of TB in the cohort between 1985 (0.45 per 100 PY) and 1989 (2.67 per 100 PY) and a stabilization around 1.5–2.0 per 100 PY until 1993. Pulmonary TB was estimated to increase the AIDS cumulative incidence by 0.4% when performing a simulation with the 1993 AIDS case definition. Single drug resistance was documented in 3.4% of the cases and a multiple drug resistance in 5.1%.ConclusionTB incidence has stabilized since 1990 in the Aquitaine cohort with a limited increase of the number of AIDS cases (1993 CDC criteria). Drug resistance was rare.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo investigate the relative risk of occupational HIV transmission for surgeons practising in tropical Africa compared with their western colleagues.Design and settingFrom June to November 1993, a prospective study was performed at St Francis' Hospital, Katete, Zambia (350-bed hospital which serves a community of 300 000 people).MethodsThe HIV seroprevalence among consecutive surgical patients and the incidence of occupational parenteral exposures to blood during surgery were prospectively studied in a Zambian district hospital. HIV seroprevalence was determined by taking blood from the surgical patients on admission into the operating theatre. Serum was stored at −20°C and transported to the Academic Medical Centre of the University of Amsterdam, where the presence of HIV antibodies was tested by enzyme immunoassay and seropositive samples confirmed by Western blot. Number of parenteral exposures during the study period was scored by interviewing the seven surgeons and their personnel after each surgical procedure about accidental parenteral exposures to blood. The total number of parenteral exposures per surgeon per year was obtained by extrapolation. The cumulated risk of seroconversion due to parenteral blood exposure can be calculated as: 1 -(1 -fp)ny, wherefis the population seroprevalence, p the chance of transmission per incident (estimated to be 0.46%),nthe number of parenteral exposures per year andythe years of practice.ResultsHIV seroprevalence in the surgical patient group was 22.3%. Twelve parenteral exposures to blood (surgeons, n = 8; other personnel, n = 4) took place in 1161 operations. Number of parenteral exposures per surgeon was extrapolated to three per year. The non-dominant index finger was exposed in 10 out of the 12 parenteral exposures. Based on these data, the risk of contracting HIV infection for a surgeon practising in Zambia for 5 years is 1.5%. The risk for a surgeon working in a western hospital whenf= 0.23%,n= 20 per year (5.6% of 350 operations) andy= 5 is estimated at 0.1%.ConclusionsAlthough occupational exposure rate was relatively low, the HIV seroprevalence was so high that the relative cumulated seroconversion risk for surgeons in tropical Africa is estimated to be 15 times higher than in western countries. This implies that health-care organizations should bear in mind that each year one out of 300 employees working in tropical Africa may become occupationally infected with HIV.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo determine the efficacy of zidovudine (ZDV) in preventing decline of neurocognitive functions in HIV-1 infection.DesignRetrospective evaluation of subjects enrolled in a natural history study. Two analyses were made to evaluate the effect of (1) current ZDV, irrespective of length of treatment and (2) long-term ZDV treatment for at least 1 year.SettingSubjects were recruited from HIV out-patient clinics.PatientsHIV-1 -seropositive subjects were assigned to one of three groups according to the Centers for Disease Control and Prevention classification: asymptomatic infection (n = 60), symptomatic infection but without AIDS (n = 51), and AIDS (n = 32).Main outcome measuresStandardized neuropsychological and neurophysiological measures [electroencephalogram (EEG) and long-latency evoked potentials].ResultsLong-term ZDV use was associated with improved cognitive performance in subjects with early symptomatic HIV-1 infection and AIDS, compared to subjects in the same clinical stage but without previous ZDV treatment. This was corroborated by neurophysiological evidence of reduced slow-wave EEG amplitude in the ZDV-treated subjects. The advantage of ZDV treatment was evident despite lower immune status in most treated subjects.ConclusionsThe findings in this natural history study indicate that long-term ZDV treatment may be an effective prophylactic to reduce neurocognitive deficits in symptomatic HIV-1 infection, thereby lowering the risk for developing HIV-1-associated dementia.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID