Efficacy of antiretroviral inhibitors in HIV cell-to-cell transmission

抗逆转录病毒抑制剂在 HIV 细胞间传播中的功效

基本信息

批准号：
8599743
负责人：
WALTHER H MOTHES
金额：
$ 8.33万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8599743
关键词：
Acquired Immunodeficiency Syndrome Adherence Adopted Adverse effects Affect Anti-Retroviral Agents Antiretroviral drug resistance Antiviral Agents Antiviral Therapy Baltimore Binding Binding Sites Biological Assay Capsid Cells Dose Drug resistance Effectiveness Evaluation Evolution Exhibits Gene Expression Generations HIV HIV Entry Inhibitors Health Highly Active Antiretroviral Therapy Infection Integrase Inhibitors Laboratories Lead Life Light Measures Molecular Conformation Multi-Drug Resistance Nucleosides Patients Pharmaceutical Preparations Protease Inhibitor Proviruses Regimen Relative (related person)Reporting Resistance Shapes Site Stream Testing Viral Viral Genes Virus antiretroviral therapy chemotherapy compare effectiveness compliance behavior drug efficacy inhibitor/antagonist insight neutralizing antibody non-nucleoside reverse transcriptase inhibitors public health relevance receptor research study response transmission process virological synapse

项目摘要

DESCRIPTION (provided by applicant): Many AIDS patients can now expect to live a long life because highly active antiretroviral therapies (HAART) effectively suppress HIV replication to undetectable levels. However, chemotherapy is associated with severe side effects that affect long-term health, is very expensive, and as such interferes with adherence by patients. Therefore, there is a continued need to develop and optimize therapy regimens to lessen side effects, promote better adherence, and increase the relative drug efficacy. The Baltimore and the Trkola laboratories have recently questioned the effectiveness of antiretroviral therapies and neutralizing antibodies during HIV cell-to-cell transmission. Cell-to-cell transmission allows efficient viral spreading via sites of cell-cell contact designated virological synapses. Importanty, it increases the number of proviruses in infected target cells thereby leading to higher viral gene expression as compared to infections by cell-free HIV. The higher effective local MOI leads to a high multiplicity of infection that can result in the increased resistance of cell-to-cell transmision to antiviral therapies. These recent observations require a re-evaluation of commonly used antiretroviral therapies against HIV cell-to-cell transmission. Here we propose to systematically test the effectiveness of numerous antiretroviral inhibitors against HIV cell-to-cell transmission. We hypothesize that the observed resistance to anti-retroviral drugs depends on the inhibitory potential of the drug. Drugs with high inhibitory potential may be the most effective against cell-to-cell transmission of HIV. We will apply a highly sensitive and quantitative assay that measures HIV cell- to-cell transmission as a necessary first step to re-evaluate the efficacy of commonly used antiretroviral inhibitors. Our experiments have the potential to further optimize existing HAART regimens.

描述（由申请人提供）：许多艾滋病患者现在可以期望长寿，因为高效抗逆转录病毒疗法（HAART）可以有效地将艾滋病毒复制抑制到不可检测的水平。然而，化疗会产生严重的副作用，影响长期健康，而且非常昂贵，因此会影响患者的依从性。因此，需要持续开发和优化治疗方案以减少副作用、促进更好的依从性并提高相对药物疗效。巴尔的摩和特科拉实验室最近质疑抗逆转录病毒疗法和中和抗体在艾滋病毒细胞间传播过程中的有效性。细胞间传播允许病毒通过指定的病毒突触的细胞间接触位点进行有效传播。重要的是，它增加了受感染靶细胞中原病毒的数量，从而导致更高的病毒基因表达与无细胞HIV感染相比。较高的有效局部 MOI 会导致较高的感染复数，从而导致细胞间传播对抗病毒治疗的抵抗力增加。这些最近的观察结果需要重新评估常用的抗艾滋病毒细胞间传播的抗逆转录病毒疗法。在这里，我们建议系统地测试多种抗逆转录病毒抑制剂对艾滋病毒细胞间传播的有效性。我们假设观察到的抗逆转录病毒药物耐药性取决于药物的抑制潜力。具有高抑制潜力的药物可能是对抗艾滋病毒细胞间传播最有效的药物。我们将应用一种高度灵敏的定量测定来测量 HIV 细胞间传播，作为重新评估常用抗逆转录病毒抑制剂功效的必要第一步。我们的实验有可能进一步优化现有的 HAART 方案。