ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo investigate viral properties that contribute to the pathogenic potential of HIV-2 in macaques.DesignWe compared HIV-2/287, a virus highly pathogenic inMacaca nemestrina,with its non-pathogenic progenitor HIV-2 EHO, for coreceptor usage and ability to infect human and macaque peripheral blood mononuclear cells (PBMC).MethodsCoreceptor usage was determined in GHOST cells expressing known coreceptors, and in PBMC with coreceptor-specific inhibitors. Infectivity in PBMC was determined by virus titration and p27 antigen production. Early and late products of reverse transcription were measured by PCR with primers specific for the long terminal repeat (LTR), or thegagregion, respectively.ResultsBoth viruses preferentially infect HOS-CD4 cells expressing CXCR4. Inhibition by CXCR4-specific peptide TW70 and monoclonal antibody 12G5 indicated that both viruses use predominantly CXCR4 to infect macaque and human PBMC. HIV-2/287 showed greater infectivity than HIV-2 EHO in macaque cells, but the situation was reversed in human cells. Kinetic analysis of reverse transcription products revealed no restriction in reverse transcription following HIV-2 EHO infection of macaque PBMC. However, comparison of the level of newly initiated HIV-2 EHO DNA in macaque and human PBMC indicated that there is an early restriction, prior to the initiation of reverse transcription.ConclusionsResults indicate that the adaptation of HIV-2 EHO inM. nemestrinato a highly pathogenic virus HIV-2/287 is not correlated with a shift in or an expansion of coreceptor usage, but with the acquisition of an ability to overcome restrictions for growth in macaque PBMC.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveHIV-1 infection in humans has been reported to lead to a shift in the cytokine balance, with a relative decrease in T helper 1 type cytokines, especially IL-2. On the basis of the expression of CD45RA, in combination with homing markers CD62L or α4β7, T helper cells can be sub-divided into naive, activated naive, central memory and effector memory cells as well as gut-homing subpopulations. In addition, each subset may have the potential to express distinct cytokines. At present it is unclear whether the changes in cytokine expression observed in HIV-1-infected individuals are secondary to changes within the composition of CD4 T cell subsets or are caused by changes in cytokine expression within each subset.Materials and methodsA new technique was developed to detect cytokine expression in phorbol 12-myristate 13-acetate/ionomycin-activated CD62L and α4β7-expressing CD4 T cell subsets, using the protease inhibitor KD-IX-73-4.ResultsIn SIV-infected macaques that develop AIDS a marked decrease in IL-2 expression was found within central, effector, or gut-homing memory cell subsets, whereas the expression of IL-2 in naive T cell subsets remained unaffected. This reduced IL-2 expression by memory cells and not a loss of the frequency of CD4 memory cells accounted for the reduced expression of IL-2 by CD4 T cells during SIV infection.ConclusionAs defined by the cell surface markers utilized, it appears that progression to AIDS is associated with functional impairment of memory cells, but not changes in lymphocyte circulation patterns.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundThe hallmark of HIV infection is the involution and destruction of lymphoid tissue. However, very little information exists on the effect of highly active antiretroviral therapy (HAART) on lymphoid tissue structure.ObjectiveTo evaluate the effect of a HAART regimen after 48 weeks on the architecture and cell regeneration of tonsil lymphoid tissue in HIV-infected patients with CD4 T cell counts ⩾ 500/μl.MethodsFrom June 1997 to February 1998 all asymptomatic HIV-infected patients with CD4 T cell counts ⩾ 500/μl seen at our unit were offered quadruple antiretroviral therapy. Tonsil biopsies were obtained at baseline and at 48 weeks. Tonsil tissue sections were examined to evaluate structural and immunohistochemical changes by two blinded and independent pathologists. Cell numbers were counted for selected markers in T-dependent zones.ResultsEleven patients were evaluable, six were excluded because of insufficient or inadequate sampling in at least one of the biopsies. Cellular depletion, plasma cell accumulation and prominent vessels were observed in all cases; three excluded patients with evaluable baseline biopsies showed similar tissue lesions. Follow-up biopsies demonstrated some degree of improvement in all patients. Germinal centres appeared in seven cases that were not seen at baseline. CD4 cell counts increased and CD8 cell counts decreased significantly in lymphoid tissue. An increase in CD45RA+ cells was observed; however, the proportion of CD45+Ki67+ cells did not differ between baseline and 48 weeks.ConclusionThis study shows an unexpected range of moderate to severe lymphoid tissue lesions in mildly immunosuppressed HIV-infected patients, which was partly restored after 48 weeks of HAART.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundRelatively little is known about the long-term durability of viral suppression in individuals initially achieving a viral load of less than 50 copies/ml within 24 weeks of starting antiretroviral therapy, nor the extent to which therapy interruption accounts for the loss of suppression.MethodsWe intensely followed all 336 antiretroviral-naive patients attending the Goethe Universitat Clinic who began multi-drug combination regimens and in whom a viral load of less than 50 copies/ml was achieved within 24 weeks, in order to assess the risk of viral load rebound. Inspection of case notes allowed the distinction of viral rebound according to whether there was an associated complete interruption of therapy.ResultsA total of 61 patients experienced viral rebound during 543.1 person-years of follow-up, giving a 25.3% risk of rebound by 3.3 years from first achieving viral suppression. However, for 47 of the patients with viral rebound there was an associated documented complete interruption of antiretroviral therapy, mostly as a result of co-morbidities, leaving 14 who appear to represent a failure of the virological efficacy of therapy (viral breakthrough; 5.2% risk by 3.3 years). The risk of viral breakthrough declined with the increased duration of suppression (P= 0.01).ConclusionThe intrinsic virological effectiveness of multi-drug antiretroviral therapy in previously drug-naive individuals appears to be such that viral suppression, once achieved, can be maintained for several years in patients not interrupting therapy. The major challenge is to develop regimens that can be taken consistently and safely for such long periods of time.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo assess the factors associated with virologic response to non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens in a large clinic cohort.DesignInception cohort.SettingHIV clinics in EuropePatientsWe identified all patients in EuroSIDA who began a regimen including either nevirapine or efavirenz (not both) after July 1997 and for whom pre-therapy viral load and CD4 cell count were known.Main outcome measuresVirological failure.ResultsA total of 1325 patients initiated nevirapine and 878 efavirenz. Respectively, median start dates were October 1998 and May 1999. Other factors at baseline, including CD4 cell count, viral load, previous AIDS, previous antiretroviral drug use and make-up of the NNRTI-containing regimen were all approximately similar between the nevirapine and efavirenz groups. A total of 669 patients experienced virological failure during follow-up. In a Cox model, less protease inhibitors and nucleoside reverse transcriptase inhibitors (NRTIs) previously used, higher CD4 nadir, lower viral load at baseline, a previous AIDS diagnosis and less NRTIs in the regimen were associated with lower risk of virological failure. The relative hazard of virological failure comparing those on efavirenz with those on nevirapine was 0.57 (95% confidence interval, 0.47–0.69;P< 0.0001).ConclusionsThe difference in virologic outcome between those using nevirapine and efavirenz in this almost entirely drug-experienced population could reflect differences in effectiveness of the drugs in this setting but, despite the similarity between groups at baseline, bias cannot be excluded as an explanation. Replication of these findings in randomized trials and other cohort studies is required.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundLong-term therapy with protease inhibitors (PI) is associated with hypertriglyceridaemia, low high-density lipoprotein (HDL) levels and accumulation of apolipoprotein (apo) E- and apo C-III-containing lipoproteins.ObjectivesTo evaluate the impact, on this dyslipaemic phenotype, of three polymorphisms of the apo C-III gene: two on an insulin response element and one in the 3′-region. Apo E genotypes were evaluated also.DesignSixty consecutive male patients attending the HIV follow-up consultation were included during a 3-month period. All patients received at least one PI. Apo C-III and apo E genotypes were determined. Besides routine bio-clinical examination, a detailed exploration of lipoproteins and of insulin secretion markers was carried out.MethodsPlasma lipoparticles, insulin, proinsulin and C-peptide were measured by specific immuno-assays. Determination of apo C-III genotypes (−455C/T, −482C/T andSstI) and of apo E alleles (&epsis;2, &epsis;3 and &epsis;4) were performed by amplification and endonuclease digestion and were confirmed by allele-specific oligonucleotide hybridization.ResultsDistribution of apo C-III alleles defined four major haplotyes. Carriers of the −455C variant had 30% lower levels of HDL-cholesterol than non-carriers. Plasma triglycerides increased according to the number of variant alleles. In multivariate analysis, a model including age, body mass index, clinical stage and treatment length, plasma insulin and apo C-III haplotypes explained around 43% of the HDL-cholesterol and triglycerides variability. Measurements of lipids before and after the use of PI demonstrated synergistic effects of the treatment and apo C-III variants on triglyceride levels.ConclusionsApo C-III polymorphisms might identify a genetic predisposition to develop dyslipidaemia under PI therapy.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundProtease inhibitor-containing antiretroviral therapy for the treatment of HIV-1 infection is associated with elevated triglyceride and low-density lipoprotein (LDL)-cholesterol levels which may expose patients to an increased risk of coronary artery disease (CAD). We report the lipid and lipoprotein profiles of a representative subset of treatment-naive patients included in the Atlantic Study. This study compares patients treated with stavudine and didanosine plus the random addition of either the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), the protease inhibitor indinavir or the nucleoside reverse transcriptase inhibitor lamivudine.MethodsLipids and lipoproteins were quantified from prospectively collected and cryopreserved plasma samples obtained at weeks 0, 6 and 24.ResultsWe observed a striking increase in high-density lipoprotein (HDL)-cholesterol (49%), apolipoprotein AI (19%), lipoprotein AI (38%) and HDL particle size (3%) in the NVP-treated patients (n = 34) at week 24. Much less pronounced changes in these parameters were seen to a similar extent both in patients receiving lamivudine (n = 39) and indinavir (n = 41). LDL-cholesterol also increased significantly both in the NVP and indinavir arms, but only in the NVP arm was this offset by a significant reduction (14%) in total over HDL-cholesterol ratio. Using a multivariate linear regression model, adjusting for CD4 cell count and plasma HIV RNA both at baseline and during treatment, randomization to the NVP-containing arm remained significant in explaining the observed changes in HDL-cholesterol and other HDL-related parameters.ConclusionsIn HIV-1 infected patients treated with a regimen of stavudine, didanosine and NVP we found changes in lipids and lipoproteins which are associated with a sharp decrease in risk for CAD in other settings. If confirmed in larger studies, these findings both may influence the initial choice of therapy for HIV-1 infection, and might lead to novel approaches targeted at raising HDL-cholesterol for CAD prevention.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundCombined use of dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) allows a precise estimate of regional body composition and intra-abdominal adipose tissue (IAT). Data on body composition in HIV-infected children (HIV+) receiving highly active antiretroviral therapy (HAART) with (LD+) and without (LD–) lipodystrophy are lacking.MethodsDXA scans were performed in 34 HIV+: six LD+, 28 LD– and 34 pair-matched (age, sex and body mass index) healthy controls (HC): six for LD+ (HC+) and 28 for LD– (HC–). MRI scans were performed in 16 HIV+: six LD+, 10 LD– and 16 pair-matched (age and sex) HC. Data were analysed by analysis of variance,post hocFisher test and Mann–Whitney test.ResultsLD+ and LD– were similar for: previous exposure to zidovudine/zidovudine + didanosine, months on HAART (stavudine + lamuvidine + one protease inhibitor), CD4+ cells, patients with HIV-RNA < 50 copies/ml. In HIV+ and HC, fat mass and distribution were significantly different, whereas lean mass was comparable. Thus, LD+ and LD– as compared to HC+ and HC– respectively showed: (1) reduced fat amount and percentage; (2) lower truncal fat mass; (3) markedly reduced limbs fat mass. Within the HIV+ group, (4) LD+ showed higher fat trunk/fat total (P= 0.04) and lower fat limbs/ fat total ratios (P= 0.009) than LD–; (5) LD+ showed larger IAT areas than LD– and HC (P< 0.0003).ConclusionsIncreased central fat and peripheral lipoatrophy are distinctive features of all HAART-treated children. Changes in body fat composition are detectable by DXA even in the absence of signs of Lipodystrophy. Only LD+ show true central obesity.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo determine the effect of adjuvant prednisolone use on the development of abacavir (ABC)- and nevirapine (NVP)-associated hypersensitivity reactions (HSR).MethodsRandomized open-label study in antiretroviral-naive adult HIV-1infected patients using a factorial design in which NVP and/or hydroxyurea (HU) and/or prednisolone are added to a regimen of ABC, zidovudine and lamivudine. Prednisolone (40 mg once daily) was added for the first 2 weeks of treatment. As it was difficult to distinguish ABC-associated HSR from NVP-associated HSR, these events were treated as a composite endpoint. The odds ratio (OR) of developing HSR for prednisolone-use was calculated with and without stratification by NVP and/or HU. Logistic regression was performed to identify risk factors for developing HSR.ResultsOf the 229 patients 115 were randomized to prednisolone and 114 to no-prednisolone; 19 (17%) and 11 (10%) patients, respectively, developed HSR. The expected prevention of HSR by prednisolone use was not observed. In fact use of prednisolone showed an increased risk for HSR although this did not reach statistical significance [OR, 1.82; 95% confidence interval (CI), 0.82–4.03]. There was a higher incidence of HSR in the NVP group than in the non-NVP group (20% versus 6%;P= 0.002). An additional risk factor identified in a multivariate logistic model was a high baseline CD4 cell count (OR, 1.26 per 100 × 106cells/l increase; 95% CI, 1.06–1.51).ConclusionsThe simultaneous start of ABC and NVP in first-line antiretroviral regimens should be avoided because of a high (20%) incidence of HSR. Short-term therapy with prednisolone did not prevent HSR in patients using ABC with or without NVP.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID