摘要:

ObjectiveTo derive reliable estimates of the sensitivity of HIV-1 DNA polymerase chain reaction (PCR) in the neonatal period and to quantify the relative contributions of intra-uterine and intra-partum transmission.MethodsAfter reviewing studies on the early diagnosis of HIV-1 infection, investigators were asked to provide published and unpublished PCR test results on prospectively followed, non-breastfed, vertically infected children. Age-specific estimates of the sensitivity of PCR were derived using distribution-free methods for interval-censored data.ResultsData on 271 infected children were combined for analysis. PCR detected HIV-1 DNA in an estimated 38% [90% confidence interval (CD, 29–46] of HIV-infected children tested on the day of, or day after, birth. Sensitivity was observed to rise rapidly in the second week of life, reaching 93% (90% Cl, 76–97) by 14 days of age.ConclusionThe sensitivity of PCR in the neonatal period is higher than previously reported. This affects the clinical interpretation of an early negative test result and encourages the use of PCR as an endpoint for trials to evaluate interventions to reduce vertical transmission in non-breastfed populations. Approximately one-third of vertically acquired HIV-1 infection could be attributable to intra-uterine transmission.

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 characterize the transcellular transport of HIV-1 Tat. HIV-1 Tat contains a putative localization signal and no leader peptide; however, it can be released from virus-infected cells and taken up by uninfected cells.Design and methodsWe constructed a chimeric protein between Tat and dihydrofolate reductase (DHFR), a cytosolic enzyme that binds tightly to the folate analogue methotrexate (MTX). As confirmed by protease sensitivity assays, binding to MTX results in stabilization of the three-dimensional structure of the DHFR domain. The nuclear translocation of recombinant proteins was monitored by both functional [transcellular transactivation of a long terminal repeat-chloramphenicol acetyl transferase (LTR-CAT) reporter gene] and biochemical (subcellular localization in HeLa cells of exogenous radiolabelled proteins) assays and the effects of MTX-induced stabilization were evaluated.ResultsWhen in vitro translated proteins are added to HeLa cells in culture, both wild-type Tat and the chimeric protein Tat-DHFR are taken up by target cells and accumulate in the nucleus, unlike wild-type DHFR. Cells transfected with Tat-DHFR, when co-cultured with cells harbouring a LTR-CAT gene, induce transactivation of the reporter gene to the same extent as cells expressing wild-type Tat. These findings indicate that Tat can mediate the internalization of unrelated polypeptides. Pre-treatment of Tat-DHFR with MTX blocks the nuclear translocation of the chimeric protein. MTX has no effect on wild-type Tat.ConclusionHIV-1 Tat can act as a vector to drive polypeptides into the nucleoplasm of living cells. The inhibitory effects of MTX on the nuclear localization of Tat-DHFR suggest that an unfolding step is required for the internalization of exogenous Tat.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo relate the expression of HIV regulatory proteins and HIV-specific mRNA in the brain cells of infected individuals with clinical neurological disease.DesignFormalin-fixed postmortem brain tissue from 14 HIV-infected adult patients, with previous repeated neurological and neuroradiological examinations, was studied by immunohistochemical and molecular biological methods. Samples from non-infected brains served as controls.MethodsImmunohistochemistry with monoclonal antibodies (MAb) was combined with in situ RNA hybridization. Target cells were identified with MAb to glial fibrillary acidic protein (GFAP; astrocytes), CD68 (activated macrophages) and Ricinus communis agglutinin (RCA-1; microglia, endothelial cells). For HIV, a panel of MAb against HIV Nef, Tat, Rev and Env proteins or probes specific for all classes of mRNA (net), for singly or non-spliced mRNA (env) and for non-spliced mRNA (gag/pot) were used.ResultsNef protein was detected in subcortical or subpial astrocytes in seven out of 14 samples, and in multinucleated giant cells in two cases. Gag/pol or env mRNA-expressing astrocytes were detected in four cases. In four out of five cases studied, HIV Rev, but not Tat, was also expressed in astrocytes. Six out of the seven patients with Nef-positive astrocytes had suffered from moderate to severe dementia. The patient with most rapidly progressing severe dementia showed extensive HIV mRNA expression together with Nef and Rev expression in astrocytes.ConclusionIn adult human brain, astrocytes are infected by HIV and preferentially express HIV Nef and Rev proteins but are also sometimes productively infected. Astrocyte infection is associated with moderate to severe dementia which agrees with recent knowledge on the housekeeping activities of astrocytes and their eventual role in learning and memory.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectivesTo investigate both small and large intestinal permeability in HIV-positive subjects, and correlate variation in intestinal mucosal abnormality with immunological and nutritional markers of HIV disease.MethodsSmall and large intestinal permeability studies were performed in 14 HIV-seropositive patients and eight healthy men. Eight out of the 14 patients had diarrhoea and all subjects were negative for enteropathogens. Small intestinal permeability was determined using the lactulose-mannitol test and large intestinal permeability using the colonic absorption of51Cr-EDTA. In addition, CD4 cell count, β2-microglobulin, C-reactive protein estimation and anthropometry were carried out in all subjects.ResultsHIV-seropositive subjects had higher lactulose-mannitol ratios (LMR; 0.084±0.007 versus 0.013±0.0008) and lower51Cr activity (1.986±0.066 versus 3.115±0.560) than controls (P<0.0004 and P<0.05, respectively). Colonic uptake of51Cr-EDTA was no different between subjects with and those without diarrhoea (2.04±0.124 versus 1.92±0.143; P> 0.05). A negative correlation was found between LMR and51Cr-EDTA, but only for patients with diarrhoea (r=-0.81; P=0.015).ConclusionRegional variation affecting intestinal absorptive function occurs in patients with HIV-related diarrhoea and is characterized by increased LMR and reduced colonic uptake of51Cr-EDTA. The pathogenesis and clinical significance of such changes are unknown.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectivesTo examine whether the route of immunization determines the hierarchy of T-cell epitope proliferative responses in macaques.DesignMacaques were immunized with a recombinant simian immunodeficiency virus (SIV) p27core protein by the intramuscular, male and female genital or rectal route, each of which was augmented by oral immunization, and by the novel targeted lymph-node immunization route. Overlapping peptides were used to identify the proliferative T-cell epitopes and to determine their hierarchy in the circulation, spleen and lymph nodes.MethodsT-cell epitope mapping of the proliferative responses was studied in short-term cell lines. Dendritic cells and macrophages were enriched by metrizamide gradient and adherence to plastic, respectively.ResultsIntramuscular immunization elicited in the circulating T cells a hierarchy of T-cell epitopes within four peptides in the following descending order of frequency: peptides 121–140 (57.9%), 41–60 (28.9%), 61–80 (18.9%) and 101–120 (5.4%). The hierarchy of these four T-cell epitope responses differed significantly with each of the five routes of immunization, when circulating (P<0.001), splenic (P<0.02-<0.001) or iliac lymph-node cells (P<0.001) were analysed. The effect of antigen-presenting cells was then investigated and enriched dendritic cells were more effective than macrophages in processing and presenting the p27antigen and the immunodominant (121–140) and 61–80 T-cell epitopes.ConclusionsThe route of immunization may determine the hierarchy of T-cell epitopes in the lymph nodes draining the mucosa in the circulating and splenic lymphocytes. The diversity of T-cell epitopes may affect the control of HIV at different anatomical sites, the administration route of the vaccine, and selection of polypeptides or recombinant antigens for immunization.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo evaluate the efficacy and safety of zidovudine (ZDV) and lymphoblastoid interferon (IFN)-α combination therapy compared with ZDV monotherapy in HIV-infected subjects with CD4+ cell counts between 150 and 500x106/1.DesignOpen, randomized controlled trial with subjects stratified by the Centers for Disease Control and Prevention (CDC) 1986 classification of HIV disease (group 11/111 or IV). The study was amended to a sequential design in February 1992 to allow interim analyses to be conducted.SettingOutpatient clinics in 45 hospitals in Europe, Australia and Canada.ParticipantsA total of 402 previously untreated subjects with symptomatic HIV infection (CDC group IV) and CD4+ count 150–500xT06/1 or asymptomatic HIV infection (CDC group 11/111) with CD4+ count 150–350 x 106/l.InterventionsZDV 250 mg twice daily with or without 3 MU subcutaneous injections of lymphoblastoid IFN-α three times per week.Main outcome measuresTime to development of a study endpoint defined as: progression from CDC group 11/111 to group IV, group IV non-AIDS to AIDS, or group IV AIDS to a second AIDS-defining condition; also CD4+ count to < 50x 106/1 on two occasions at least 1 month apart or HIV-related death irrespective of CDC group on entry.ResultsThere was no reduction in the rate of disease progression for patients receiving ZDV plus IFN-α compared with patients receiving ZDV alone. No major differences between the groups were seen for CD4+ counts or percentages, or p24antigenaemia. In a subset of 70 patients, a similar proportion from both dose groups showed evidence of ZDV resistance after 48 weeks of treatment. More adverse experiences were seen in the ZDV/IFN-a group.ConclusionsCombination therapy with low dose lymphoblastoid IFN-α and ZDV revealed no clinical benefit compared with ZDV monotherapy.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo evaluate the risk of developing tuberculosis or other AIDS-related diseases (ARD) in HIV-infected patients treated with corticosteroids as adjunctive therapy for Pneumocystis carinii pneumonia (PCP).DesignRetrospective study.SettingInfectious Disease Service of a 1000-bed university teaching hospital in Barcelona, Spain.PatientsHIV-infected patients diagnosed with PCP from 1985 to 1992. Patients were classified into two groups: steroid (group A) and non-steroid (group B) adjunctive therapy. Baseline characteristics, antibiotherapy, dose and duration of steroidal treatment were analysed. Endpoints were either the development of tuberculosis or other ARD or death.ResultsFrom the 129 patients included in this study 72 were in group A and 57 in group B. No differences between groups were observed in baseline characteristics or mean follow-up period (15 versus 14 months, respectively).“ The mean total dose of steroids was 420 mg ‘(range, 160–1260 mg) methylprednisolone or its equivalent in dexamethasone, with a mean treatment duration of 12 days (range, 4–33 days). No differences were found in the occurrence of tuberculosis or other endpoints in the first 6 months of follow-up. In addition, the cumulative rate of developing tuberculosis was 7% in group A and 12% in group B at 12 months of follow-up, and 13 versus 12% at 24 months (P= 0.622, Mantel-Cox): 4 versus 4% at 12 months and 27 versus 24% at 24 months (P= 0.873) for non-tuberculosis mycobacterial infection, and 40 versus 42% at 12 months, and 88 versus 66% at 24 months (P=0.330) for non-mycobacterial ARD. The cumulative survival rate was 79 versus 71% and 46 versus 34% at 12 and 24 months, respectively (P= 0.526).ConclusionsOur data suggest that the use of corticosteroids during PCP in HIV-infected patients at the doses and for the duration used in our patients did not enhance the risk of developing or relapsing tuberculosis or other ARD.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo repeat and extend findings suggesting that sleep disturbance, excessive daytime sleepiness, and degraded cognitive-motor abilities may be early markers of central nervous system (CNS) involvement in HIV infection.DesignA controlled, cross-sectional, prospective analysis.SettingClinical research center at a teaching hospital and a military health research center.SubjectsTwenty-three HIV-positive (mean CD4+ count, 387 ± 162 × 106/l) and 13 seronegative men who were Naval personnel or participants of the University of California, San Diego HIV Neurobehavioral Research Center.Main outcome measuresNocturnal and daytime sleep electroencephalogram, electromyogram, and electrocardiogram. Simple and complex cognitive-motor performance assessed via computerized tasks.ResultsComparison of sleep parameters based on HIV status, length of time infected, zidovudine use, and CD4+ count indicated that CD4+ T cells >400x106/l were associated with a distortion in nocturnal sleep characterized by increased stages 3 and 4 non-rapid eye movement (i.e., slow-wave) sleep in the latter portion of the night and reduced nocturnal awakenings. HIV-positive patients were no sleepier in the daytime than controls. Cognitive-motor performance revealed deficits in both accuracy and efficiency for HIV-positive patients.ConclusionAsymptomatic HIV-positive patients with CD4+ counts >400x106/l demonstrate a statistically significant increase in slow-wave sleep during the latter portion of the night and less arousability. CD4+ lymphocyte count in the early phases of HIV infection appears to differentiate between various levels of HIV disease progression with respect to certain CNS measurements of nocturnal sleep and cognitive-motor performance. Sleep structure distortion remains one of the earliest and most consistently replicable physiological signs of HIV infection. This distortion may provide a link to immune function, disease progression, and cognitive-motor disability in HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

ObjectiveTo determine whether nutritional status affects immunological markers of HIV-1 disease progression.DesignA longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with β2-microglobulin (β2M; AIDS index) over an 18-month follow-up.MethodsBicohemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B,, B2/ Be, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and β2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model.ResultsDevelopment of deficiency of vitamin A or vitamin B12was associated with a decline in CD4 cell count (P= 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12and zinc was associated with higher CD4 cell counts (P= 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by ziddvudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P= 0.041) and the AIDS index (P= 0.005).ConclusionsThese data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.

ISSN:0269-9370    

出版商:OVID    

年代:1995

数据来源: OVID