HIV Coreceptor Switching

HIV辅助受体转换

• 批准号: 7902978
• 负责人: DONALD E MOSIER
• 金额: $ 30.08万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7902978
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Address; Antibody Formation; Antiviral Agents; Autologous; Binding; Biological; Biological Assay; CCR5 gene; CXCR4 gene; Cells; Chronic; Clinical Trials; Dendritic Cells; Development; Ensure; Event; Evolution; Extracellular Domain; Frequencies; Generations; Genetic Determinism; Grant; HIV; HIV Envelope Protein gp120; HIV-1; Immune; Individual; Infection; Kinetics; Laboratories; Link; Maps; Mutate; Mutation; Myelogenous; N-terminal; Patients; Pattern; Phase III Clinical Trials; Physiological; Prevalence; Probability; Property; Proteoglycan; Reporting; Research Personnel; Research Project Summaries; Resistance; Sampling; Seminal; Series; Serum; Site; Staging; Testing; Time; Vaccines; Variant; Viral; Virus; cohort; cost; fitness; glycosylation; inhibitor/antagonist; microbicide; mutant; neutralizing antibody; polysulfated glycosaminoglycan; pressure; programs; receptor; research study; syndecan-4; transmission process; vaccine development

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.

描述（由申请人提供）：项目摘要 - 本研究计划解决了与HIV信封糖蛋白GP120相关的两个问题。首先是选择性压力，有利于在初次感染时传播CCR5使用（R5）HIV-1。这些研究对于定义围绕传播的选择压力很重要，对于疫苗开发和CCR5抑制剂在微生物剂中的潜在使用至关重要。我们将表征一系列主要的传播包络克隆，然后使用它们来检验两个假设：（1）在传播的生理条件下，传播病毒更加稳定，（2）选择性感染髓样树突状细胞有利于R5病毒。第二个问题涉及允许长时间感染后50％的患者中允许50％患者出现CXCR4的选择性力。我们将表征从早期到末期感染的一系列纵向信封，并使用它们来检验四个其他假设：（1）cocector转换的概率受信封演变以使CCR5的不同细胞外域的方式影响； （2）仅当抗体对包膜的反应消失时，仅出现CXCR4使用的变体（R5x4或X4病毒）； （3），R5病毒的演变在某些患者中达到了健身天花板，随后是适应性突然丧失，允许X4病毒变异出现而无需竞争； （4），与硫酸化的糖胺聚糖结合的结合会促进croecector的转换。将映射负责这些功能更改的包络序列。这些实验与在III期临床试验中接近CCR5抑制剂的接近使用高度相关，并且很可能可以预测对这类抗病毒药的抗性的可能性。