ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

BackgroundA key factor leading to impaired immunity in HIV infection is an alteration of the pattern of cytokine response, although its precise nature remains controversial, particularly thein vivoinfluence of HIV on interleukin (IL)-12 synthesis.DesignA cross-sectional study in 73 HIV-infected persons (28 of them receiving highly active antiretroviral therapy) and 18 HIV-seronegative healthy donors.MethodsThe frequency of monocytes/macrophages (M/M) synthesizing IL-12, IL-10 and tumour necrosis factor α (TNF-α) was determined in peripheral blood mononuclear cells. The cells were cultured in medium or were stimulated with lipopolysaccharide; proportions of CD64 M/M producing IL-12, TNF-α or IL-10 was determined by cytofluorometric analysis. The influence of exogenous interferon γ (IFN-γ), IL-10 or IL-15 on IL-12 synthesis was tested.ResultsChronic HIV disease is associated with increased priming of M/M for IL-12 (involving both p40 and p70 molecules) and TNF-α synthesis; this was associated with cosynthesis of both cytokines by a fraction of M/M. Priming for IL-12 was physiologically enhanced by IFN-γ and decreased by IL-10; IL-15 had no effect. The proportion of IL-10-producing CD64 M/M was not altered in patients compared with controls but there was an inverse correlation between IL-10-producing M/M and viral load. IL-12 production was not correlated with viral load but was increased following antiretroviral therapy. Following LPS stimulation, IL-12 and TNF-α responses were not altered in HIV-positive patients; however, the IL-10 response was decreased but restored by antiretroviral therapy.ConclusionThese observations argue for a preserved intrinsic CD64 M/M of IL-12 production in HIV pathogenesis.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo evaluate the immunogenicity and efficacy of an inactivated dual-subtype feline immunodeficiency virus (FIV) vaccine.DesignSpecific-pathogen-free cats were immunized with dual-subtype (subtype A FIVPetand subtype D FIVShi) vaccine and challenged with eitherin vivo- orin vitro-derived FIV inocula.MethodsDual-subtype vaccinated, single-subtype vaccinated, and placebo-immunized cats were challenged within vivo-derived heterologous subtype B FIVBang[10–100 50% cat infectious doses (CID50)],in vivo-derived homologous FIVShi(50 CID50), andin vitro- andin vivo-derived homologous FIVPet(20–50 CID50). Dual-subtype vaccine immunogenicity and efficacy were evaluated and compared to single-subtype strain vaccines. FIV infection was determined using virus isolation and proviral PCR of peripheral blood mononuclear cells and lymphoid tissues.ResultsFour out of five dual-subtype vaccinated cats were protected against low-dose FIVBang(10 CID50) and subsequently againstin vivo-derived FIVPet(50 CID50) challenge, whereas all placebo-immunized cats became infected. Furthermore, dual-subtype vaccine protected two out of five cats against high-dose FIVBangchallenge (100 CID50) which infected seven out of eight single-subtype vaccinated cats. All dual-subtype vaccinated cats were protected againstin vivo-derived FIVPet, but only one out of five single-subtype vaccinated cats were protected againstin vivo-derived FIVPet. Dual-subtype vaccination induced broad-spectrum virus-neutralizing antibodies and FIV-specific interferon-γ responses along with elevated FIV-specific perforin mRNA levels, suggesting an increase in cytotoxic cell activities.ConclusionDual-subtype vaccinated cats developed broad-spectrum humoral and cellular immunity which protected cats againstin vivo-derived inocula of homologous and heterologous FIV subtypes. Thus, multi-subtype antigen vaccines may be an effective strategy against AIDS viruses.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTest the efficacy of a mixture of six NEF (N1, N2, N3), GAG (G1, G2) and ENV (E) lipopeptides in the induction of B- and T-cell anti-HIV responses.DesignA randomized phase I open-label dose-finding trial. Twenty-eight healthy seronegative volunteers received the lipopeptides, with or without the adjuvant QS21.MethodsAnti-HIV-peptide antibodies were detected by enzyme-linked immunosorbent assay and Western blotting. Induction of cellulary responses was assessed by proliferative test and51Cr-release assay.ResultsLocal and systemic adverse reactions were always mild or moderate. After three injections an antibody response was detected in 25 out of 28 volunteers (89%). T cells from 19 (79%) of the 24 volunteers proliferated in response to at least one peptide. The majority of the volunteers had induced a multispecific proliferative response; that is, cells from volunteers proliferated to two (five of 19), three (five of 19), four (three of 19) or five peptides (one of 19). Cytotoxic responses by anti-HIV CD8+ lymphocytes could be tested in 24 volunteers, 13 (54%) of whom had clear and reproducible responses, with strong activity in the remaining 12 (> 20% of specific lysis), and polyepitopic responses were detected in at least seven of the 13 responders. Cytotoxic responses were found against the whole NEF protein (clade B LAI) in three of four tested volunteers and cross-reactions with the proteins of clade B (MN) and clade A (Bangui) HIV-1 strains, and also HIV-2 ROD, were detected in one of two tested volunteers.ConclusionsLipopeptides are promising immunogens for an AIDS vaccine.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveStructured antiretroviral treatment interruption (STI) has been advocated as a therapeutic strategy for HIV-1 infection. We report initial observations of cerebrospinal fluid (CSF) HIV-1 infection in five patients undergoing serial lumbar punctures (LPs) during STI undertaken following virological failure.Design and methodsIn this prospective observational study we quantified HIV-1 RNA concentrations and assessed both phenotypic drug susceptibility profiles and genotypic antiviral drug resistance mutations in CSF and plasma during the period of treatment interruption. CSF white blood cells were also counted, and patients’ neurological status monitored.ResultsIn four of the patients, CSF HIV-1 concentration increased more rapidly than that of the plasma, with consequent reduction in the ratio between plasma and CSF viral loads (pVL : cVL). Three individuals developed robust, though asymptomatic CSF lymphocytic pleocytosis. In all patients the predominant HIV-1 quasispecies shifted simultaneously in CSF and plasma from a drug-resistant to a more drug-susceptible phenotype with identical and simultaneous changes in genotypes associated with drug resistance.ConclusionsSTI may be accompanied by previously unrecognized changes in tissue viral exposures and lymphocyte traffic. Hence, despite ‘virological failure’ as evidenced by persistent plasma viremia, ongoing antiretroviral treatment prior to its interruption appeared to suppress CSF HIV-1 infection (indeed more effectively than that of plasma) and restrain lymphocyte traffic into the CSF. Simultaneous change of resistance mutations in CSF and plasma was likely due to re-emergence and overgrowth of pre-existing strains with ready exchange of virus between these two compartments, either facilitated by or provoking a local CSF lymphocytosis.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesTo assess the incidence and risk factors for hepatotoxicity associated with nevirapine.DesignA prospective cohort study in a teaching and referral hospital involving all consecutive patients who were prescribed a nevirapine-containing antiretroviral regimen between September 1997 and May 2000.MethodCutaneous and hepatic adverse reactions and clinical hepatitis were assessed. Blood analysis including plasma HIV-1 RNA CD4 cell counts, liver chemistry tests, and serology for hepatitis B and C viruses. Hepatotoxicity was defined as an increase of at least threefold in serum alanine aminotransferase or aspartate aminotransferase levels compared with baseline values.ResultsOf a total of 610 patients, 82 (13.4%) were antiretroviral naive when commencing nevirapine, and 46.2 and 8.9% were coinfected with hepatitis C and B viruses, respectively. Median duration of exposure to nevirapine was 8.7 months (interquartile range 3.4–14.3). Hepatotoxicity developed in 76 (12.5%), an incidence of 13.1/100 person-years. Kaplan–Meier estimated incidence of hepatotoxicity at 3, 6 and 12 months was 3.7, 9.7 and 20.1%, respectively. In seven (1.1%) patients, hepatotoxicity was associated with clinical hepatitis, which was reversible upon discontinuation of therapy. Multivariate analysis identified the duration of prior exposure to antiretroviral drugs, hepatitis C virus, and higher baseline levels of alanine aminotransferase as independent risk factors for hepatotoxicity.ConclusionsHepatotoxicity but not clinical hepatitis was common in HIV-1-infected patients receiving nevirapine-containing regimens and the incidence steadily increased over time. Prolonged exposure to any antiretroviral therapy, coinfection with hepatitis C virus and abnormal baseline levels of alanine aminotransferase identified patients at a higher risk.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo evaluate the development of phenotypic and genotypic resistance to zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents.DesignAll patients were enrolled in a double-blind controlled randomized trial (the INCAS study) and were selected for detailed resistance studies based on specimen availability and virologic response.MethodsWithin the three study groups (zidovudine/nevirapine, zidovudine/didanosine or zidovudine/nevirapine/didanosine), 16, 19 and 24 patients, respectively, had evaluable baseline isolates and remained in the study > 24 weeks. Phenotypic resistance to all three drugs was evaluated using the VIRCO recombinant virus assay. Genotypic sequencing was done on selected specimens from patients receiving zidovudine/nevirapine/didanosine.ResultsAfter 24 weeks, all available isolates taken from patients receiving nevirapine were resistant to this agent, while 18/21 (86%) patients receiving triple therapy carried such isolates at 30–60 weeks. At 24 weeks, zidovudine resistance developed in 4/40 isolates but was more frequent after 30–60 weeks, especially in patients on two drugs. The degree of zidovudine resistance (rise in concentration required for 50% inhibition) appeared lower in the triple therapy group compared with zidovudine/didanosine (P= 0.0004). All nevirapine-resistant isolates that were sequenced carried at least one mutation associated with resistance, most often K103N and/or Y181C.ConclusionThe use of highly active drug therapies may be associated with a beneficial effect on the development of antiretroviral drug resistance. The characteristics of virologic suppression that must be maintained to avoid resistance are currently being studied in hypothesis-driven clinical trials.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Background and objectivesTo determine the factors contributing to changes in bone mineral density (BMD) over time in HIV-infected patients receiving highly active antiretroviral therapy (HAART).MethodsAnalyses of lumbar spine BMD in 183 male Caucasian participants in the Western Australian HIV Cohort study, comprising a longitudinal analysis of data from 54 patients on stable HAART regimens, and a cross-sectional analysis comparing data from 131 protease inhibitor (PI)-treated patients and 52 PI-naive (including 28 antiretroviral treatment-naive) patients.ResultsAverage lumbar spine BMD remained stable or increased over the time frame considered. Although there was no evidence of a change of average BMD over time in patients receiving nelfinavir (P= 0.92), there was evidence of increasing bone density in the indinavir group (average increase, 0.31z-score per year;P< 0.001). Lower initialz-scores in the longitudinal analysis were significantly associated with lower pre-HAART BMI (P= 0.003), consistent with results of the cross-sectional analysis in which lowest BMI prior to initial dual X-ray absorptiometry scan was associated with decreased BMD (P= 0.02, overall group). Although PI therapy was also associated with decreased BMD in a univariate analysis of the cross-sectional data (P= 0.04), this effect was abrogated in a multiple linear regression analysis (P= 0.11) with lowest BMI remaining significant (P= 0.04).ConclusionsWe found no evidence, overall, of accelerated bone loss in patients treated with nelfinavir- or indinavir-containing HAART regimens, and propose that indinavir therapy may be associated with an increase in bone mineral density over time. Pre-HAART BMI was an independent and powerful determinant of an individual's initialz-score in the longitudinal analysis, and adjustment for this effect in a cross-sectional analysis abrogated the association between PI therapy and decreased lumbar spinez-score.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo describe HIV-infected individuals taking antidepressants who developed the serotonin syndrome due to drug–drug or drug–food interactions.Design and settingCase studies carried out at the HIV Outpatient Clinic, Atlanta Veterans Affairs Medical Center.Participants and interventionsHIV-positive patients who were receiving antiretroviral and antidepressant therapies and presented with symptoms consistent with the serotonin syndrome. Their antidepressants were discontinued or the doses reduced in order to resolve the symptoms.ResultsFive cases of serotonin syndrome developed after patients who were taking antidepressants ingested P450 inhibitors.ConclusionsSerotonin syndrome should be suspected in patients on serotonergic medications who present with mental status change, autonomic dysfunction, and neuromuscular abnormalities. Suspicion should be heightened in those who are ingesting substances known to inhibit P450 enzymes, such as protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and grapefruit juice.

ISSN:0269-9370    

出版商:OVID    

年代:2001

数据来源: OVID