AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS Preadipocytes from healthy donors were assessed for prol...AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors(NRTIs), nonnucleoside reverse transcriptase inhibitors(NNRTIs), and protease inhibitors(PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase(GPDH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher's Least Significant Difference test. RESULTS Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI(14% at 48 h, P < 0.001) and PI + NRTI(19% at 48 h, P < 0.001) with additional suppression when ritonavir(RTV) was added(26% at 48 h). The drug combination of atazanavir(ATV) + RTV + emtricitabine(FTC) + tenofovir(TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity(64%) or lipid accumulation(39%), P < 0.001. Combining NRTIs with a PI(ATV + FTC + TDF) significantly suppressed differentiation(GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added(ATV + FTC + TDF + RTV, P < 0.001). CONCLUSION Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.展开更多
There have been few reports evaluating the prevalence of genotypic mutations and antiretroviral resistance among chronic HIV-infected Veterans within the United States. This retrospective cross-sectional study charact...There have been few reports evaluating the prevalence of genotypic mutations and antiretroviral resistance among chronic HIV-infected Veterans within the United States. This retrospective cross-sectional study characterizes the rates and changes in HIV genotypic mutations and antiretroviral resistance among viremic patients from 2001 to 2006 at the VA Medical Center located in Washington, DC. The District of Columbia is the metropolitan area with the highest HIV prevalence within the United States. De-identified, linked HIV RNA, genotypic reverse transcriptase (RT) and protease (Pr) mutations and antiretroviral resistance results were assessed for changes during the 6-year period. Aggregated clinic and antiretroviral utilization, and HIV acquisition risk data were evaluated for patients in care during this time. Among 990 viremic samples, the rate of any detected RT or Pr mutation fell from 100% in 2001 to 95% in 2006. This was primarily attributable to the 15% - 20% decrease seen for RT gene mutations against nucleoside/nucleotide class and non-nucleoside class during this period. Resistance to didanosine, stavudine, zidovudine, nevirapine and efavirenz decreased, and tenofovir resistance increased. Despite stable rates of Pr gene mutations, atazanavir resistance increased by 22% from 2003 to 2006. Some but not all changes in genotypic mutations and resistance patterns reflected our patients’ antiretroviral drug utilization. As sexual contacts (77%) and injection drug use (22%) were the leading acquisition risks disclosed by our HIV-infected patients, the high prevalence and changing patterns of HIV genotypic mutations and drug resistance among these patients have had pivotal impacts not only on HIV treatment but potential transmission into our community.展开更多
【目的】构建I型人类免疫缺陷病毒(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂(nonnucleoside reverse transcriptase inhibitors,NNRTIs)的药效团模型,通过对中药化学数据库(traditional Chinese medicine dat...【目的】构建I型人类免疫缺陷病毒(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂(nonnucleoside reverse transcriptase inhibitors,NNRTIs)的药效团模型,通过对中药化学数据库(traditional Chinese medicine database,TCMD)的搜索,在中药中寻找新型抗耐药的NNRTIs。【方法】从已知的NNRTIs与逆转录酶复合物的晶体结构出发,通过构象分析和药效团识别等方法,构建NNRTIs的药效团模型并检验其可靠性;基于药效团模型对TCMD进行数据库搜索,发现新型潜在的NNRTIs。【结果】从PDB中检索出2010年至2014年RT与NNRTIs复合物的晶体结构30个,从中抽提出其活性配体,建立了一个包含30个活性配体的小分子数据库;通过对上市药物TMC278和TMC125及高活性抑制剂DJZ的构象叠合和药效特征基团分析构建了新的NNRTIs药效团模型,该模型包含了5个药效特征基团;以符合这5个药效特征基团中任意4个为条件,在活性配体小分子数据库中验证性搜索出18个化合物,检出率为60.0%;基于五点药效团模型对TCMD进行数据库搜索得到272个化合物。【结论】以TMC278、TMC125和DJZ构建的五点药效团模型,以符合其中任意4个为条件,在活性配体小分子数据库中的检出率达到60.0%,表明所建药效团模型是可靠的。展开更多
目的:探究影响人类免疫缺陷病毒Ⅰ型(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂6-苄基-1-乙氧甲基-5-异丙基尿嘧啶[6-benzyl-1-(ethoxymethyl)-5-isopropyluracil,MKC-442]及其类似物抗病毒活性的主要分子微...目的:探究影响人类免疫缺陷病毒Ⅰ型(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂6-苄基-1-乙氧甲基-5-异丙基尿嘧啶[6-benzyl-1-(ethoxymethyl)-5-isopropyluracil,MKC-442]及其类似物抗病毒活性的主要分子微观结构因素。方法:针对45个MKC-442及其类似物,利用遗传函数逼近法(genetic function approximation,GFA)构建10个抗HIV-1活性与优选的分子结构描述符之间的二维定量构效关系(2-dimensional quantitative structure-activity relationship,2D-QSAR)模型,从中挑选出最优模型并对其进行验证,据此阐明影响MKC-442及其类似物抗HIV-1活性的主要微观结构因素。结果:最优2D-QSAR模型的非交叉验证相关系数r2为0.7845,交叉验证相关系数q2为0.6958,预测验证相关系数r2pred为0.8415,表明其具有较高的预测能力和稳定性。结论:研究表明,MKC-442及其类似物抗HIV-1活性主要与描述符JursFNSA2,ShadowYZ,DipoleX,Kappa3AM和CHIV3P相关,为MKC-442及其类似物的进一步结构修饰打下了一定的理论基础。展开更多
HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibit...HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.展开更多
文摘AIM To investigate the mechanism(s) by which potential effects of multi-drug highly-active antiretroviral therapy contributes to lipodystrophy syndrome. METHODS Preadipocytes from healthy donors were assessed for proliferation and differentiation in the presence of nucleoside reverse transcriptase inhibitors(NRTIs), nonnucleoside reverse transcriptase inhibitors(NNRTIs), and protease inhibitors(PIs) individually and in combination. Effects on proliferation were assessed with a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and effects on differentiation were assessed from glycerol-3-phosphate dehydrogenase(GPDH) activity and quantitation of Oil Red O staining for intracellular lipid. Data were analyzed with a randomized block ANOVA with post-hoc Fisher's Least Significant Difference test. RESULTS Preadipocyte proliferation was inhibited by a combination of NNRTI + NRTI(14% at 48 h, P < 0.001) and PI + NRTI(19% at 48 h, P < 0.001) with additional suppression when ritonavir(RTV) was added(26% at 48 h). The drug combination of atazanavir(ATV) + RTV + emtricitabine(FTC) + tenofovir(TDF) had the greatest inhibitory effect on proliferation at 48 h. Preadipocyte differentiation was most significantly reduced by the efavirenz + FTC + TDF assessed either by GPDH activity(64%) or lipid accumulation(39%), P < 0.001. Combining NRTIs with a PI(ATV + FTC + TDF) significantly suppressed differentiation(GPDH activity reduced 29%, lipid accumulation reduced by 19%, P < 0.01). This effect was slightly greater when a boosting amount of RTV was added(ATV + FTC + TDF + RTV, P < 0.001). CONCLUSION Although combination antiretroviral therapy is clinically more efficacious than single drug regimens, it also has a much greater inhibitory effect on preadipocyte proliferation and differentiation.
文摘There have been few reports evaluating the prevalence of genotypic mutations and antiretroviral resistance among chronic HIV-infected Veterans within the United States. This retrospective cross-sectional study characterizes the rates and changes in HIV genotypic mutations and antiretroviral resistance among viremic patients from 2001 to 2006 at the VA Medical Center located in Washington, DC. The District of Columbia is the metropolitan area with the highest HIV prevalence within the United States. De-identified, linked HIV RNA, genotypic reverse transcriptase (RT) and protease (Pr) mutations and antiretroviral resistance results were assessed for changes during the 6-year period. Aggregated clinic and antiretroviral utilization, and HIV acquisition risk data were evaluated for patients in care during this time. Among 990 viremic samples, the rate of any detected RT or Pr mutation fell from 100% in 2001 to 95% in 2006. This was primarily attributable to the 15% - 20% decrease seen for RT gene mutations against nucleoside/nucleotide class and non-nucleoside class during this period. Resistance to didanosine, stavudine, zidovudine, nevirapine and efavirenz decreased, and tenofovir resistance increased. Despite stable rates of Pr gene mutations, atazanavir resistance increased by 22% from 2003 to 2006. Some but not all changes in genotypic mutations and resistance patterns reflected our patients’ antiretroviral drug utilization. As sexual contacts (77%) and injection drug use (22%) were the leading acquisition risks disclosed by our HIV-infected patients, the high prevalence and changing patterns of HIV genotypic mutations and drug resistance among these patients have had pivotal impacts not only on HIV treatment but potential transmission into our community.
文摘【目的】构建I型人类免疫缺陷病毒(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂(nonnucleoside reverse transcriptase inhibitors,NNRTIs)的药效团模型,通过对中药化学数据库(traditional Chinese medicine database,TCMD)的搜索,在中药中寻找新型抗耐药的NNRTIs。【方法】从已知的NNRTIs与逆转录酶复合物的晶体结构出发,通过构象分析和药效团识别等方法,构建NNRTIs的药效团模型并检验其可靠性;基于药效团模型对TCMD进行数据库搜索,发现新型潜在的NNRTIs。【结果】从PDB中检索出2010年至2014年RT与NNRTIs复合物的晶体结构30个,从中抽提出其活性配体,建立了一个包含30个活性配体的小分子数据库;通过对上市药物TMC278和TMC125及高活性抑制剂DJZ的构象叠合和药效特征基团分析构建了新的NNRTIs药效团模型,该模型包含了5个药效特征基团;以符合这5个药效特征基团中任意4个为条件,在活性配体小分子数据库中验证性搜索出18个化合物,检出率为60.0%;基于五点药效团模型对TCMD进行数据库搜索得到272个化合物。【结论】以TMC278、TMC125和DJZ构建的五点药效团模型,以符合其中任意4个为条件,在活性配体小分子数据库中的检出率达到60.0%,表明所建药效团模型是可靠的。
文摘目的:探究影响人类免疫缺陷病毒Ⅰ型(human immunodeficiency virus type 1,HIV-1)非核苷类逆转录酶抑制剂6-苄基-1-乙氧甲基-5-异丙基尿嘧啶[6-benzyl-1-(ethoxymethyl)-5-isopropyluracil,MKC-442]及其类似物抗病毒活性的主要分子微观结构因素。方法:针对45个MKC-442及其类似物,利用遗传函数逼近法(genetic function approximation,GFA)构建10个抗HIV-1活性与优选的分子结构描述符之间的二维定量构效关系(2-dimensional quantitative structure-activity relationship,2D-QSAR)模型,从中挑选出最优模型并对其进行验证,据此阐明影响MKC-442及其类似物抗HIV-1活性的主要微观结构因素。结果:最优2D-QSAR模型的非交叉验证相关系数r2为0.7845,交叉验证相关系数q2为0.6958,预测验证相关系数r2pred为0.8415,表明其具有较高的预测能力和稳定性。结论:研究表明,MKC-442及其类似物抗HIV-1活性主要与描述符JursFNSA2,ShadowYZ,DipoleX,Kappa3AM和CHIV3P相关,为MKC-442及其类似物的进一步结构修饰打下了一定的理论基础。
基金supported by the grants from Chinese National Science Foundation(No.30472166)the Tianjin Commission of Sciences and Technology under the Contract(No.06YFGZSH07000)
文摘HIV- 1 RT is an important target for the treatment of AIDS. There are two major classes of antiviral agents that inhibit HIV- 1 RT have been identified, nucleoside RT inhibitors （NRTIs） and non-nucleoside RT inhibitors （NNRTIs）. In this report, a noval class of non-nucleoside compound with potential RT inhibitory activity were found from the traditional Chinese medicines database （TCMD） using a combination of virtual screening, docking, molecular dynamic simulations, where results were ranked by scoring function of the docking tool. The result indicates that M4753 （a compound derived from TCMD） has not only the lowest bonding energy but also the best match in geometric conformation with the forthcoming NNRTIs. Accordingly M4753 might possibly become a promising lead compound of NNRTIs for AIDS therapy.
