ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo quantify the effect of HIV infection and HIV-suppressive therapy on interferon-α (IFN-α) production by human blood mononuclear cells; to compare, in parallel, effects on CD4+ T-cell numbers; and to ascertain the relationship of these interferon and CD4 parameters to resistance to opportunistic infections.DesignSerial studies of 294 unselected patients with HIV infection during therapy, with outcomes analysis.MethodsDetermination of IFN generation by blood mononuclear cells via bioassay, and T-lymphocyte subset analysis via flow cytometry; serial studies of individual patients; linear regression and χ2contingency table analysis.ResultsHIV burden is inversely related to interferon-α generation, much as it is to CD4+ T-cell counts. Both of these recover during HIV-suppressive therapy. Reconstitution of IFN-α generation to levels commensurate with protection against opportunistic infection occurs prior to similar restoration of CD4 counts. In the outcomes analyses, such immune reconstitution was associated with protection from recurrent or new opportunistic infection. Conversely, viral suppression without such immunologic recovery was not protective against opportunistic infection.ConclusionsRapidly responding IFN-α generating cells appear to participate in resistance to opportunistic intracellular infection. Recovery of IFN-α generation may be an early marker of immune reconstitution in AIDS.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundHIV-1 strains R5 and X4 can infect CD4 memory T cellsin vivo. Anti-CD3/28 stimulation induces β-chemokines and CCR5 down-regulation and renders these cells resistant to R5 HIV-1 infection. Here we describe an additional cellular mechanism that blocks productive R5 HIV-1 infection of CD4 memory T cells.MethodsBlood-derived CD4 memory T cells and CD4 T-cell clones were infected with primary R5 and X4 HIV-1 strains. Virus replication was correlated with CCR5 expression and β-chemokine production. Virus entry and infectivity were measured by PCR for early and late products of HIV reverse transcription respectively.ResultsR5 strains were up to 1000-fold less infectious than X4 viruses for CD4 memory T cells. This resistance was independent of CCR5 levels and of the Δ-32 mutation and theCCR2-V64I/CCR5-59653T linked mutations. Blocking endogenous β-chemokines relieved minimally this restriction. At the single cell level, CD4 memory cells were either permissive or non-permissive for R5 HIV-1 infection. R5 HIV titre was up to 10-fold lower than X4 virus titre even in a permissive clone. However, R5 viruses replicated as efficiently as X4 viruses in the permissive clone when neutralizing anti-β chemokine antibodies were added. Non-permissive cells blocked a post-entry step of the virus life-cycle and expressed early but not late HIV transcripts. Neutralizing anti-β chemokine antibodies promoted R5 virus replication marginally in the non-permissive clone.ConclusionSome blood memory CD4 T cells retard R5 HIV-1 replication via endogenous β-chemokines whereas others block productive R5 HIV-1 infection by an additional mechanism that interferes with a post-entry step of the virus life cycle. These natural barriers might contribute to lower pathogenicity of R5 HIV-1 strains for CD4 memory T cells than X4 viruses that emerge late in disease.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Objective and designWe have recently shown that the number of CCR5 molecules at the surface of peripheral blood CD4 T cells (CCR5 density) correlates with the viral RNA plasma level in HIV-1-infected individuals. As viral load is a strong predictor of outcome in HIV infection, the present study examines the correlation between CCR5 density and HIV-1 disease progression.MethodsUsing a quantitative flow cytometry assay, we measured CCR5 density in HIV-1-infected adults and control healthy volunteers. The CCR5 genotype (presence of a Δ32 allele) was also determined.ResultsCCR5 density was stable over time on non-activated, HLA-DR−CD4 T cells of infected individuals. In a study cohort of 25 patients, asymptomtic and non-treated, we observed a correlation between CCR5 density on HLA-DR−CD4 T cells and the CD4 T cell slope (P= 0.026), which was independent of the presence or absence of the Δ32CCR5 deletion. In particular, slow progressors expressed lower CCR5 densities than non-slow progressors (P= 0.004) and non-infected control subjects (P= 0.002).ConclusionThese results are compatible with the hypothesis that CCR5 density, which is a key factor of HIV-1 infectability, determines in-vivo HIV production, and thereby the rate of CD4 cell decline. Consequently, CCR5 density quantitation could be a new valuable prognostic tool in HIV-1 infection. Moreover, these data emphasize the therapeutic potential of treatments that reduce functional CCR5 density.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo determine if low level, persistent, HIV-1 replication within specific immune cells contributes to HIV-1-specific immune responsiveness.DesignWe analyzed 59 HIV-1-infected subjects on stable highly active antiretroviral therapy (HAART) therapy (not including zidovudine) with suppressed plasma viremia (< 400 copies/ml) for phenotypic and lymphoproliferative correlates of immune function.MethodsPeripheral blood mononuclear cells were collected for immunophenotyping, lymphoproliferative assays, and simultaneous immunophenotyping/ultrasensitivein situhybridization. Plasma was collected for plasma viral load as determined by the Ultra Sensitive Roche Amplicor RT–PCR. Descriptive statistics (mean and SD, median, first and third quartiles) were determined for all variables in two groups defined as having persistent viral replication present or absent. The two-sided Wilcoxon test (continuity correction, 0.5) was used to compare lymphocyte phenotypes, lymphoproliferative assay responses, intracellulargag-polmRNA, lowest CD4 counts and CD4% of these two groups.ResultsHIV-1 replication in CD4, CD45RO memory T lymphocytes persists in spite of undetectable plasma viral load. Patients (n = 24) with persistent intracellular expression of HIV-1 mRNA (> 0.3%) showed significantin vitroproliferative responses to HIV-1 p24 (stimulation index ⩾ 10) compared to patients (n = 35) without persistent intracellular replication. The group with persistent HIV-1 replication in cells showed no significant response to the recall antigen tetanus toxoid but a trend toward higher responses to pathogen antigens. There were no differences between the groups in the prevalence of AIDS or occurrences of opportunistic infections; however, the high viral persistence group was more HAART experienced (P< 0.05).ConclusionsThese results suggest that HIV-1-specific immune responses correlate with evidence of ongoing HIV-1 replication.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesThe management of HIV infection has greatly improved during recent years essentially because of the appearance of new antiretroviral drugs. Highly active antiretroviral therapy (HAART) has achieved important reductions of viraemia and significant recoveries of CD4+cell counts in HIV-infected patients. Nonetheless, cases of HIV-infected individuals experiencing lipodystrophy (LD) are being increasingly reported. The purpose of this work was to analyse whether the presence of mitochondrial abnormalities is a frequent feature in LD, since we previously detected mitochondrial abnormalities in an HIV-patient. The second main objective was to study whether LD could be associated with a specific drug.DesignSeven HIV patients presenting LD and five HIV non-LD controls participated in the study. LD patients met the following criteria: (1) LD was their only clinical abnormality, (2) LD was clinically relevant, (3) compliance with antiretroviral treatment was higher than 90% and (4) patients did not have personal or familial history suggestive of mitochondrial disease or neuromuscular disorder.MethodsHistological stainings, histo-enzymatic reactions, enzymatic and respiratory activities of mitochondrial respiratory chain complexes, and mitochondrial DNA (mtDNA) depletion and rearrangements were examined on muscle mitochondria.ResultsStructural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients.ConclusionsThe mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo assess whether drug-induced suppression of the plasma viral load is associated with selective differential distribution of virus-specific CD8 T cells between the blood and secondary lymphoid organs.MethodsHIV-specific CD8 T lymphocyte responses were quantified in matched peripheral blood and lymph node samples from seven patients starting treatment shortly after infection, who received antiretroviral theray (ART) for a median of 14 months. Cells recovered from samples were subjected to IFN-γ ELISPOT analysis. A series of synthetic peptides corresponding to previously characterized cytotoxic T lymphocyte epitopes restricted by HLA I molecules present in each patient were used as antigens, together with appropriate positive and negative controls.ResultsHIV-specific CD8 T lymphocyte responses were found in six of the seven patients. The observed frequencies of HIV-specific CD8 T lymphocytes and the pattern of epitope recognition was identical within the two compartments. These results also confirm the observation that functional HIV-specific CD8 T cells are preserved on ART in most patients initiating treatment at the time of primary HIV-1 infection.ConclusionThis investigation demonstrated that patterns of antigenic immunodominance as well as frequencies of HIV-specific CD8 T lymphocytes are similar in blood and lymphoid tissue compartments in HIV-infected individuals. These findings support current approaches to the identification of HIV-specific CD8 T lymphocyte reactivity based on leukocytes isolated from blood even in patients with ART-induced suppression of viral load.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo quantify the percentage of the two major subpopulations of blood dendritic cells (DC) in HIV-1-seropositive Ugandan individuals infected with non-clade B viruses and compare this with that seen in clade B HIV-1 infected non-African individuals. DC maturation/activation status was also investigated via the expression of CD86.MethodsThe percentage of blood DC was quantified by using flow cytometry. DC were identified as the lineage (CD3, CD14, CD16, CD19, CD20, CD56)-negative, HLA-DR-positive population and the two major subpopulations were differentiated by CD11c expression.ResultsThe percentage of blood DC was reduced significantly in HIV-1-seropositive African individuals when compared with controls (0.21 and 0.39% respectively). A similar reduction was also seen in non-African patients residing in the UK (0.19% compared with 0.36% for controls). However, there was no selective loss in either CD11c-positive or CD11c-negative subpopulations. The percentage of blood DC expressing CD86 was significantly greater in HIV-1-seropositive individuals when compared with controls and the increased expression was largely confined to CD11c-negative DC.ConclusionsAfricans infected with non-clade B HIV-1 showed similar reductions in the percentage of blood DC to non-Africans infected with clade B viruses. There was no selective loss of either DC subpopulation, suggesting that the ability of DC to acquire and present antigens or to produce interferon-α may both be impaired in HIV-1 infection.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesSuccessful highly active antiretroviral therapy (HAART) is usually associated with a rapid decline in HIV plasma RNA levels and a gradual increase in CD4 T cells. We examined whether changes in cytokine production and profile precede other immunological changes and whether these might occur in temporal association with plasma HIV RNA changes.Design and methodsEleven HIV-1-infected patients were enrolled into a prospective cohort study; eight patients were naive to antiretroviral therapy. Blood samples were collected pre-therapy (week 0) and at 1, 2, and 3 weeks post-initiation of therapy.ResultsAll 11 patients enrolled remained on triple HAART for 1 week, eight for 2 weeks, and six for ⩾ 3 weeks. When compared to week 0, these patients had a ⩾ 2-log10decline in HIV plasma RNA levels and/or a decline to ⩽ 400 copies/ml by week 3 of therapy (p= 0.004). The numbers and percentages of CD4 and CD8 T cells, and the percentage of naive, memory, and activated T cells did not change significantly between weeks 0 and 1 or 0 and 3. Of all the immune parameters examined only: the percentage of CD4 T cells spontaneously producing tumor necrosis factor (TNF)-α (median, 2.4 versus 0.5%P= 0.025); the percentage of CD8 T cells spontaneously producing TNF-α (median, 0.6 versus 0.2%P= 0.037); and the percentage of CD3 T cells spontaneously producing interleukin-4 (median, 1.8 versus 0.8%P= 0.004) changed significantly between weeks 0 and 3.ConclusionsIn these patients, decreases in the percentage of T cells spontaneously producing TNF-α or interleukin-4 preceded changes in CD4 T cells. If confirmed by others, these observations may be useful as early predictors of response to and early failure of HAART.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo examine the natural phenotypic variability in drug susceptibility among recombinant HIV-1 isolates from a large number of untreated HIV-positive individuals from wide-ranging geographic locations, and to use this information to establish biologically relevant cut-off values for phenotypic antiretroviral susceptibility testing.MethodsPhenotypic susceptibility to 14 antiretroviral agents was determined for HIV-1 samples from > 1000 treatment-naive individuals in seven clinical trials. Samples were from the USA (n = 351), Germany (n = 306), Canada (n = 265), and South Africa (n = 358). Geometric mean fold-resistance and confidence intervals were determined relative to a standard laboratory wild-type virus.ResultsBaseline fold-resistance was approximately log-normally distributed for all antiretroviral agents examined. There was no evidence of large geographical differences in average antiviral susceptibility. Geometric mean fold-resistance for each of 14 antiviral agents was similar (± 0.5-fold) for samples derived from the USA, Canada, Germany, or South Africa. The non-nucleoside reverse transcriptase inhibitors (NNRTI) exhibited the broadest distribution of susceptibility; approximately 97.5% of all isolates had < 2.5–4.0, < 3.0–4.5, and < 5–10 fold-decrease in susceptibility to five protease inhibitors, six nucleoside analogues, and three NNRTI, respectively. No consistent geographic pattern or clade effect (B versus C) in either the mean or the distribution of baseline antiretroviral susceptibility was observed.ConclusionsPhenotypic drug susceptibility of HIV-1 in untreated individuals varies markedly from drug to drug, with broadly similar patterns world-wide. These results have important implications in defining the ‘normal range’ of phenotypic susceptibility to antiretroviral agents and establish biologically relevant cut-off values for this phenotypic drug susceptibility test.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID