HIV Coreceptor Switching

描述（由申请人提供）：项目摘要-本研究计划解决了两个与HIV包膜糖蛋白gp 120辅助受体使用相关的问题。第一个是选择性压力，有利于在初次感染时传播使用CCR 5（R5）的HIV-1。这些研究对于确定围绕传播的选择压力非常重要，对于疫苗开发和CCR 5抑制剂在杀微生物剂中的潜在用途也非常重要。我们将描述一系列主要传播包膜克隆的特征，然后用它们来检验两个假设：（1）传播的病毒在传播的生理条件下更稳定，（2）选择性感染髓样树突状细胞有利于R5病毒传播。第二个问题解决了选择性的力量，允许在长期感染后50%的患者中出现使用CXCR 4的病毒。我们将描述从早期到晚期感染的一系列纵向包膜的特征，并用它们来检验另外四个假设：（1）辅助受体转换的可能性受到包膜进化以接合CCR 5的不同胞外结构域的方式的影响;（2）使用CXCR 4的变体（3）R5病毒的进化在一些患者中达到适应性上限，随后是适应性的突然丧失，这使得X4病毒变体在没有竞争的情况下出现;和（4）与硫酸化糖胺聚糖的结合促进辅助受体转换。负责这些功能变化的信封序列将被映射。这些实验与CCR 5抑制剂在III期临床试验中的接近使用高度相关，并且可以很好地预测对这类抗病毒药物的耐药性的概率。

DESCRIPTION (provided by applicant): Project Summary - This research plan addresses two issues relating to coreceptor use by the HIV envelope glycoprotein gp120. The first is the selective pressures that favor transmission of CCR5-using (R5) HIV-1 at the time of primary infection. These studies are important for defining the selection pressures surrounding transmission and are of great importance for vaccine development and the potential use of CCR5 inhibitors in microbicides. We will characterize a series of primary transmission envelope clones, and then use them to test two hypotheses: (1) that transmitted virus is more stable under the physiological conditions of transmission, and (2) that selective infection of myeloid dendritic cells favors R5 virus transmission. The second issue addresses the selective forces that allow emergence of CXCR4-using viruses in 50% of patients after prolonged infection. We will characterize a longitudinal series of envelopes from early to end- stage infection and use them to test four additional hypotheses: (1) that the probability of coreceptor switching is influenced by the way in which envelope evolves to engage different extracellular domains of CCR5; (2) that CXCR4-using variants (R5X4 or X4 viruses) only emerge when antibody responses to envelope disappear; (3), that evolution of R5 viruses reaches a fitness ceiling in some patients that is followed by an abrupt loss of fitness that allows X4 viral variants to emerge without competition; and (4), that binding to sulfated glycosaminoglycans promotes coreceptor switching. The envelope sequences responsible for these functional changes will be mapped. These experiments are highly relevant to the approaching use of CCR5 inhibitors in phase III clinical trials, and may well predict the probability of resistance to this class of antivirals.