6 resultados para HIV infections Treatment

em Chinese Academy of Sciences Institutional Repositories Grid Portal


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The high mortality rate of immunocompromised patients with fungal infections and the limited availability of highly efficacious and safe agents demand the development of new antifungal therapeutics. To rapidly discover such agents, we developed a high-throughput synergy screening (HTSS) strategy for novel microbial natural products. Specifically, a microbial natural product library was screened for hits that synergize the effect of a low dosage of ketoconazole (KTC) that alone shows little detectable fungicidal activity. Through screening of approximate to 20,000 microbial extracts, 12 hits were identified with broadspectrum antifungal activity. Seven of them showed little cytotoxicity against human hepatoma cells. Fractionation of the active extracts revealed beauvericin (BEA) as the most potent component, because it dramatically synergized KTC activity against diverse fungal pathogens by a checkerboard assay. Significantly, in our immunocompromised mouse model, combinations of BEA (0.5 mg/kg) and KTC (0.5 mg/kg) prolonged survival of the host infected with Candida parapsilosis and reduced fungal colony counts in animal organs including kidneys, lungs, and brains. Such an effect was not achieved even with the high dose of 50 mg/kg KTC. These data support synergism between BEA and KTC and thereby a prospective strategy for antifungal therapy.

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Trichosanthin (TCS) is a type 1 ribosome-inactivating protein (RIP) effective against HIV-1 replication. The mechanism is not clear. Present results suggested that the antiviral action tray be partly mediated through enhanced apoptosis on infected cells. TCS induced apoptosis in normal H9 cells and this action was more potent in those infected with HIV-1. In flow cytometry study, TCS induced larger population of apoptotic H9 cells chronically infected with HIV-1 in a dose-dependent manner. At TCS concentration of 25 mu g/ml. 8.4% of normal H9 cells were found to be apoptotic whereas the same concentration induced 24.5% in HIV-1 chronically infected cells. Such difference was not found in the control experiments without TCS treatment. Two other studies supported this action. Cytotoxic study showed that cell viability was always lower in HIV-1 infected cells after TCS treatment, and DNA fragmentation studs confirmed more laddering in infected cells. The mechanism of TCS induced apoptosis in normal or infected H9 cells is not clear. Results in this study demonstrated that TCS is snore effective in inducing apoptosis in HIV-1 infected cells. This may explain in part the antiviral action of TCS. (c) 2005 Elsevier Inc. All rights reserved.

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BACKGROUND: Drug resistance profiles of human immunodeficiency virus-1 (HIV-1) in treatment-naive infections have been reported in developed countries. However, little is known in developing countries, including China, especially in treatment-naive volunt

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The southeastern region of Yunnan province is a key site for drug trafficking and HIV-1 infection spread from the west of Yunnan and Laos to southeastern China. To investigate the prevalence of HIV-1 infection and hepatitis C virus (HCV) coinfection among injection drug users (IDUs) in southeastern Yunnan, three cohorts of 285 addicts, including 242 IDUs and 43 oral drug users, living in the cities of Gejiu and Kaiyuan and the county of Yanshan were studied. HIV-1 and HCV infections were detected by enzyme-linked immunosorbent assay and/or polymerase chain reaction. Data on the age, sex, risk behavior, drug use history, employment, ethnic background, and marriage status were obtained by interview. The overall prevalence of HIV-1 infection was 71.9%. The rate of HCV coinfection among 138 HIV-1-infected IDUs was 99.3%. Most HIV-infected IDUs were 20 to 35 years old (86.7%) and were ethnic Han (75.9%), suggesting that the epidemic in Yunnan is no longer confined to non-Han ethnic minorities, HIV prevalence in female IDUs (81.2%) was significantly higher than in male IDUs (68.2%) (p <.05). The prevalence of HIV infection reached 68.4% after 1 year of injection drug use. Needle/syringe sharing is the major high risk factor for the spread of HIV-1 and HCV infections. Large-scale educational campaigns are urgently needed to reduce the spread of HIV and HCV infection in these regions.

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HR212, a recombinant protein expressed in Escherichia coli, has been previously reported to inhibit HIV-1 membrane fusion at low nanomolar level. Here we report that HR212 is effective in blocking laboratory strain HIV-1IIIB entry and replication with EC50 values of 3.92±0.62 and 6.59±1.74 nM, respectively, and inhibiting infection by clinic isolate HIV-1KM018 with EC50 values of 44.44±10.20 nM, as well as suppressing HIV-1- induced cytopathic effect with an EC50 value of 3.04±1.20 nM. It also inhibited HIV-2ROD and HIV-2CBL-20 entry and replication in the μM range. Notably, HR212 was highly effective against T20-resistant strains with EC50 values ranging from 5.09 to 7.75 nM. Unlike T20, HR212 showed stability sufficient to inhibit syncytia formation in a time-of-addition assay, and was insensitive to proteinase K digestion. These results suggest that HR212 has great potential to be further developed as novel HIV-1 fusion inhibitor for treatment of HIV/ AIDS patients, particularly for those infected by T20-resistant variants.

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高效抗逆转录病毒治疗(HAART)的应用,极大的降低了AIDS发病率和死亡 率,延长了HIV感染者的生命。但HIV耐药在很大程度上影响了HAART的疗效, 耐药株的产生成为影响抗病毒治疗效果的主要因素。欧洲、美国的耐药监测技术 规范均推荐在新感染未经抗病毒药物治疗的患者中进行原发耐药检测。我国政府 于2003年底出台了艾滋病治疗的“四免一关怀”政策,陆续在全国范围内开展了大 规模的免费抗病毒治疗,监测我国未经抗病毒药物治疗HIV-1感染者中的耐药情 况可以为制定合理的用药方案和减少耐药毒株出现提供科学依据。 根据世界卫生组织(WHO)的“HIV 耐药监测指南”,无偿献血者中的HIV-1 感染者,可以认定为HIV 新诊断未治疗人群。分析了云南无偿献血者的血浆和 外周血单核细胞(PBMC),研究云南无偿献血人群的耐药状况。 已有实验室血清学方法识别HIV-1 新近感染和长期感染,用BED-CEIA 方 法,在河南、安徽、山西自愿咨询检测(VCT)人群中检出新近感染人群,进行耐 药基因研究, 对照研究了部分长期感染人群。 样品提取核酸后,巢式聚合酶链反应(nested-PCR)扩增pol 基因区(含蛋白酶 区1~99 氨基酸全长和逆转录酶区1~242 氨基酸)。PCR 产物双脱氧法测序,所 得序列与洛斯阿拉莫斯HIV 核酸序列库(Los Alamos HIV Database)标准株构建系 统进化树分析亚型;用斯坦福大学耐药数据库(Standford HIV Drug Resistance Database)分析耐药。 研究发现,云南省2005~2006 年无偿献血者中,有52 例为HIV-1 阳性,其 中49 例血浆和相应的PBMC 样品病毒基因扩增成功。序列分析表明,HIV 病毒 的亚型分布为CRF08_BC (51.0%), CRF07_BC (24.5%), CRF01_AE (20.4%)和B (4.1%);所有样品均未发现蛋白酶抑制剂(PI)耐药基因位点主要突变,只在6 例(11.7%)样品中发现7 例次PI 次要耐药位点突变;另外,在9 例(18.4%)样品中发现10 例次核苷类逆转录酶抑制剂(NRTI) 耐药突变,1 例(2.0%)发生非核苷类 逆转录酶抑制剂(NNRTI) 耐药突变;针对具体药物PI/NRTI/NNRTI 均只有1 例 有潜在的低度耐药,临床仍对药物敏感。PBMC 和血浆的病毒耐药没有显著差异。 从河南、安徽、山西27 个VCT 检测点2006~2007 年采集的10310 例样品 中,通过WB 和BED-CEIA 检测出新近感染人群63 例,分析成功50 例血浆样 品;河南VCT 长期感染样品中随机抽样,分析成功19 例样品。分析成功的69 例VCT 样品中,HIV 病毒株的亚型分布分别为B’ (95.7%),CRF01_AE(2.9%)和 C(1.4%)。上诉样品均未检出PI 主要耐药相关突变,只在26 例(37.7%)样品中存 在27 例次PI 次要耐药相关突变;3 例(4.3%)样品出现6 例次NRTI 耐药相关突 变,7 例(10.1%)样品出现8 例次NNRTI 耐药相关突变。通过与斯坦福大学耐药 数据库比对,没有发现针对PI 类药物的临床耐药;但有2 例(2.8%)针对NRTI 类 药物耐药,1 例有M184V 突变导致对拉米夫定(3TC)和氟代拉米夫定(FTC)高度 耐药;1 例样品存在T215Y、M41L、L210W 三重突变位点,对阿巴卡韦(ABC)、 去羟肌苷(ddI)和坦那夫韦(TDF)中度耐药,对齐多夫定(AZT)和司他夫定(d4T)高 度耐药;针对NNRTI 类药物,有3 例(4.3%)毒株有耐药,1 例有K103N 突变导 致对奈韦拉平(NVP)、地拉韦啶(DLV)和依菲韦伦(EFV)的高度耐药;1 例有Y188L 突变导致对NVP 和EFV 的高度耐药;1 例存在K101E 和G190A 双重突变,导 致对NVP 的高度耐药,对DLV、EFV 和依曲韦林(ETR)中度耐药。 比较长期感染和新近感染者之间的亚型和耐药,未发现显著差异。 研究结果表明,云南、河南和安徽未经治疗HIV-1 感染者中耐药处于低流行 状态。亚型分布云南无偿献血者以CRF_BC 为主,河南、安徽VCT 人群以B’ 为主。应持续在未经治疗人群中进行耐药监测。