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

描述（由申请人提供）：许多艾滋病患者现在可以预期长寿，因为高效抗逆转录病毒疗法（HAART）有效地将艾滋病毒复制抑制到无法检测的水平。然而，化疗与影响长期健康的严重副作用相关，非常昂贵，并且因此干扰患者的依从性。因此，持续需要开发和优化治疗方案以减少副作用，促进更好的依从性，并增加相对药物功效。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。细胞到细胞的传播允许通过指定的病毒学突触的细胞-细胞接触位点进行有效的病毒传播。重要的是，它增加了感染靶细胞中前病毒的数量，从而导致更高的病毒基因表达。 与无细胞HIV感染相比，更高的有效局部MOI导致感染的高度多样性，这可能导致细胞间传播对抗病毒疗法的抗性增加。这些最近的观察结果需要重新评估常用的抗逆转录病毒疗法对艾滋病毒细胞间传播。在这里，我们建议系统地测试许多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的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HIV细胞间传播最有效的药物。我们将应用一种高度敏感的定量检测方法，测量HIV细胞间的传播，作为重新评估常用抗逆转录病毒抑制剂疗效的必要的第一步。我们的实验有可能进一步优化现有的HAART方案。

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.