摘要:

Objective:To study coreceptor usage of sequential primary HIV-1 isolates in a longitudinal follow-up cohort of HIV-1-infected men to understand its contribution to pathogenesis of HIV disease.Design:Viral coreceptor usage of sequential primary isolates from HIV-1-infected individuals was examined at various timepoints and data was compared with CD4 cell counts, rates of disease progression and β-chemokine production.Methods:Fifty-eight sequential primary isolates were obtained from four rapid progressors, six late progressors, and three long-term nonprogressors (LTNP) and their coreceptor usage was examined by infection of peripheral blood mononuclear cells (PBMC) from donors with wild-type or non-functional CC-chemokine receptor (CCR)-5, and by infection of GHOST4 cells expressing CD4 and various chemokine receptors [CCR-1–CCR-5, CXC-chemokine receptor (CXCR)-4, BOB/GPR15, BONZO/STRL33]. Production of RANTES and macrophage inflammatory protein (MIP)-1β was examined using unstimulated or phytohemagglutinin (PHA)-stimulated PBMC isolated from these individuals at multiple timepoints during infection.Results:A switch from single CCR-5 coreceptor usage to multiple coreceptor usage occurred in all four rapid progressors and three out of six late progressors. In addition to the commonly used coreceptors CXCR-4, CCR-5, and CCR-3, some of the viruses isolated from patients in the terminal stage of infection also used CCR-1, CCR-2b, CCR-4, and BOB as coreceptors. The emergence of viral variants capable of utilizing multiple coreceptors generally preceded CD4 cell decline to < 200 × 106/l and correlated with the onset of AIDS. In contrast, three LTNP maintained exclusive usage of CCR-5 over a period of 7–12 years post-infection. Endogenous production of RANTES and MIP-1β by PBMC from LTNP was not significantly different from rapid and late progressors. However, PHA-driven production of both chemokines was significantly higher in LTNP, suggesting thatin vivoactivating stimuli might curtail HIV replication by inducing these chemokines.Conclusions:Viral variants capable of utilizing a broad range of coreceptors correlated with HIV-1 disease progression. In contrast, LTNP maintain exclusive usage of CCR-5 and produce higher levels of β-chemokines. Thus, both viral and host determinants leading to the emergence of viral variants capable of using an expanded range of coreceptors may be likely determinants of disease progression.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To evaluate the prognostic significance for AIDS occurrence of plasma levels of immune activation markers in comparison with and in conjunction with HIV viral load and CD4 T-cell measurements.Design:A retrospective analysis was conducted of three plasma activation markers, the soluble tumor necrosis factor (TNF) receptor II (TNF-RII), neopterin and soluble interleukin-2 receptor levels, and of CD4 T-cell levels and plasma HIV viral load.Subjects:The participants were 659 men taking part in the University of California Los Angeles Multicenter AIDS Cohort Study who were HIV-seropositive but AIDS-free in 1985.Main outcome measure:Clinically defined AIDS within 3 years. Failure time statistical regression models for the time to development of AIDS were used to assess prognostic capacity of the parameters alone and in combination.Results:All the markers had prognostic capability. The levels of the three plasma activation markers correlated well with each other (median r = 0.61). They related less well with HIV RNA plasma levels (median r = 0.50) and least well with CD4 cell levels (median r = 0.36). Furthermore, plasma marker levels were shown to be able to stratify patients for prognosis within all the major categories of CD4 T-cell and HIV RNA levels.Conclusions:Plasma levels of soluble TNF-RII and other soluble markers of immune activation have prognostic capabilities which are different from HIV and CD4 T-cell levels. Combination of a single plasma activation marker measurement (such as soluble TNF-RII) with CD4 T-cell levels improved the prognostic capability of each. A new graphic technique for presenting prognostic capability indicated that plasma soluble TNF-RII and CD4 cell levels are better prognostic factors than HIV plasma level with CD4 cells < 200 × 106/l. Inexpensive tests for one of the plasma activation markers, such as soluble TNF-RII or neopterin, can be useful for evaluations of HIV disease course, especially when expensive equipment, technical expertise and funding required for flow cytometry and for HIV load measurements are not readily available.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objectives:To assess the dynamics of neutralizing antibodies (NAb) in long-term AIDS-free HIV-1-infected subjects and establish correlations with known markers of disease progression.Design:Cross-sectional study using sera collected from long-term non-progressors (LTNP) 8 years after seroconversion or study entry. Longitudinal study using sera collected from LTNP at 0, 0.5, 1, 2, 4, 6, 8 and 10 years after seroconversion and, as controls, from rapid progressors.Methods:Individuals with documented AIDS-free HIV-1 infection for at least 8 years were evaluated for NAb against five heterologous HIV-1 primary isolates. In the cross-sectional study, serum viral RNA levels, CD4+ T-cell numbers and T-cell function were determined on samples collected during the eighth year of follow-up. For the longitudinal study, NAb were assessed in sequential sera taken from LTNP and rapid progressors.Results:Serum neutralization titres found in individual sera differed from one HIV-1 isolate to another, were detected in 49–76% of LTNP, without correlation with the coreceptor usage of the isolate, and were positively associated with CD4+ T-lymphocyte counts (P= 0.0041) and T-cell function (P= 0.04). No correlation was found between NAb and the level of viral RNA in serum or the rate of CD4+ T-cell decline. Longitudinal analysis of sera from LTNP and rapid progressors showed that although several subjects in both groups had neutralizing activity at seroconversion, it thereafter became lower or no longer detectable. NAb were again found 1–4 years later and stably persisted in LTNP, but remained undetectable or at low levels in rapid progressors.Conclusions:NAb were preferentially found in subjects with relatively preserved T-cell function and CD4+ T-cell numbers. In these individuals, neutralizing activity against heterologous isolates increased with time. These data suggest that the capacity to produce broadly NAb is a function of the integrity of the immune system.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To assess the genetic homogeneity or heterogeneity within each set ofCandida albicansisolates colonizing/infecting the oral cavities of HIV-infected patients undergoing azole therapy when changes in susceptibility to fluconazole were detected.Design:Fourteen HIV-positive patients suffering recurrent episodes of oral candidosis were prospectively followed from the first episode to the isolation of strains with decreased susceptibility to fluconazole. The strains ofC. albicansisolated either from episodes or controls throughout the prospective study were analysed.Methods:Electrophoretic karyotyping and hybridization with the repeated sequence probe 27A were used to delineate sequential isolates.In vitrosusceptibility tests to fluconazole and ketoconazole were also performed. The results obtained by DNA fingerprinting with the probe combined with computer-assisted analysis were used to assess the genetic relationships amongst the strains. In addition, comparison with the genetic relatedness of a group of geographically unrelated strains was made.Results:Isogenic populations of sequential isolates were observed only in two patients; 12 patients harboured heterogenic populations over time, although in 11 patients there was a predominant strain that was isolated more than once, and only one of these patients carried strains with a similarity index less than 80%. With the exception of two patients, each patient carried a major strain that became less susceptible to fluconazole. The similarity index for the unrelated strains was 59%.Conclusions:HIV-infected patients may carry a mixed population of strains, but the strains tend to be related to each other. The strains were maintained throughout the course of infection and at least one developed secondary resistance to fluconazole.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To examine the relationship between HIV protease genotype and altered protease inhibitor sensitivity of isolates from patients after therapy with saquinavir (SQV) in its hard gelatin formulation.Design:Forty-one post-therapy isolates and corresponding baseline samples were obtained from 37 patients in four different clinical trials after therapy with SQV for 16–147 weeks. Post-therapy isolates were selected on the basis of preliminary sequence or drug sensitivity data.Results:Fifteen out of 17 isolates without detectable Val-48 or Met-90 mutations retained sensitivity to SQV. (The remaining isolates showed only a marginal increase in median inhibitory concentration.) In addition, three out of 15 isolates with Met-90 retained sensitivity to all other protease inhibitors tested (indinavir, ritonavir, amprenavir, nelfinavir). Of the isolates showing reduced sensitivity to SQV, six out of 22 retained sensitivity to all other protease inhibitors, whereas only four out of 22 showed broad cross-resistance to all protease inhibitors tested. The reduction in sensitivity correlated closely with the presence of Val-48 or Met-90. Subsequent accessory substitutions were also linked to reduced sensitivity. However, significant linkage was observed only between mutations at residues 48 and 82 and between those at residues 82 and 74.Conclusions:Recruitment of Val-48/Met-90 mutations was not found to be synonymous with cross-resistance. Indeed, the majority of isolates with these mutations retained sensitivity to at least one protease inhibitor (Val-48, 86%; Met-90, 77%). The recruitment of accessory mutations may occur only after the selection of key resistance mutations. Furthermore, Met-90 was found to be a poor marker of cross-resistance in SQV-treated patients.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Background:Current guidelines state that the goal of antiretroviral therapy for HIV-infected individuals is to suppress plasma viral load (pVL) to below 400 copies/mlMethods:Predictors of achieving and maintaining pVL suppression were examined in a randomized trial of combinations of zidovudine, nevirapine and didanosine in patients with CD4+ T cell counts of between 200 and 600 × 106cells/I who were naive to antiretroviral therapy and AIDS-free at enrolment.Results:One hundred and four patients had pVL > 500 copies/ml at baseline and a pVL nadir below 500 copies/ml. Of these, 77 patients experienced an increase in pVL above 500 copies/ml. The median number of days of pVL suppression to below 500 copies/ml was 285 (42) for patients with pVL nadir ≤ (>) 20 copies/ml (P= 00.0001). The relative risk of an increase in pVL above 500 copies/ml associated with a pVL nadir below 20 copies/ml was 0.11 (P= 0.0001). The relative risks of an increase in pVL above 5000 copies/ml associated with a pVL nadir below 20 copies/ml or between 20 and 400 copies/ml were 0.05 [95% confidence interval (CI), 0.02–0.12] and 0.37 (95% CI, 0.23–0.61) respectively, compared with individuals with a pVL nadir > 400 copies/ml. Individuals with a pVL nadir ≤ 20 copies/ml were at a significantly lower risk of virologic failure than individuals with a pVL nadir of between 21 and 400 copies/ml (P= 0.0001).Conclusions:Our results demonstrate that suppression of pVL below 20 copies/ml is necessary to achieve a long-term antiretroviral response. Our data support the need for a revision of current therapeutic guidelines for the management of HIV infection.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To evaluate treatment response, durability and tolerance of a four-drug regimen including saquinavir and ritonavir in combination with either zidovudine/lamivudine or stavudine/lamivudine.Design:Observational cohort of HIV-positive individuals.Methods:Viral load, CD4+ and CD8+ T lymphocyte counts were assessed at intervals of 1–3 months in subjects commencing therapy between July 1996 and November 1996. Adverse events were evaluated as well as risk factors for therapeutic failures.Results:A group of 56 male patients were included and followed for 48 weeks. Of these, 66% had already taken a protease inhibitor. Viral load dropped by a median 1.98 log10HIV RNA copies/ml from baseline (interquartile range: 1.49–2.46) and became undetectable (< 400 copies/ml) in 68% of patients. Response varied: 9% were non-responders (HIV RNA reduction < 0.5 log10copies/ml) and 23% were incomplete responders (nadir of HIV RNA > 400 copies/ml). After 48 weeks, viral load remained undetectable in 49%. Median CD4+ T lymphocyte count increased from 191 × 106to 418 × 106cells/l (range, 241–537 × 106cells/l). Although protease inhibitor and nucleoside pretreatment selected for drug-resistant viral mutants, only the protease inhibitor experience was identified as a risk factor for therapeutic failure. Adverse events occurred in 73% of patients and led to a change of therapy in 9%.Conclusion:Despite advanced HIV disease and pretreatment with multiple antiretroviral drugs, a strong initial treatment response to this drug regimen was observed. However, virological failure occurred in 51% of patients after 48 weeks and frequent adverse events complicated therapy. © 1998 Lippincott Williams & Wilkins

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Objective:To verify the effectiveness of highly active antiretroviral therapy (HAART) and to identify any factors predictive of clinical outcome in a clinical setting.Design:Observational study.Methods:Treatment failure (i.e., the occurrence of new or recurrent AIDS-defining events, death or any definitive discontinuation) and the course of CD4+ cell counts and HIV RNA copies were evaluated in 250 heavily pretreated HIV-infected patients starting HAART [153 with indinavir (IDV), 55 with ritonavir (RTV), 43 with saquinavir (SQV)]. Univariate and multivariate analyses were performed to identify predictors of worse outcome.Results:During a median follow-up of 8 months, 75 patients (30%) had treatment failure because of the occurrence of an AIDS-defining event or death (n = 24), inefficacy (n = 24), or severe intolerance (n = 27). Twenty new and six recurrent AIDS-defining events, and nine deaths occurred (six out of 20 AIDS-defining events and two out of nine deaths within 1 month of treatment). CD4+ counts were above 200 × 106/l at AIDS diagnosis in only two patients. None of the SQV patients, 12 (7.8%) of the IDV patients, and 15 (27.3%) of the RTV-treated patients were considered non-compliant. The SQV-containing regimens independently correlated with treatment failure (relative risk, 2.46; 95% confidence interval, 1.20–5.03; versus IDV). Low compliance partially determined outcome in RTV-treated patients; both severe immunodepression and AIDS at baseline were predictive of treatment failure. There was a 10-fold increase in CD4+ cell counts in the patients treated with IDV and RTV; the best virological outcome occurred in IDV-treated patients, with 68.4% of patients showing undetectable HIV RNA copies after 6 months.Conclusions:HAART was effective in 70% of patients; low compliance and previous AIDS diagnosis represented predictive factors of therapy failure.

ISSN:0269-9370    

出版商:OVID    

年代:1998

数据来源: OVID