HIV entry and its inhibition

HIV进入及其抑制

• 批准号: 7636885
• 负责人: Robert W. Doms
• 金额: $ 38.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7636885
• 关键词: Affect; Anti-Retroviral Agents; Award; Binding; Biological Assay; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Count; Cells; Clinical; Clinical Trials; Collaborations; Complex; Development; Drug resistance pathway; Exhibits; Face; Failure; Generations; Goals; Grant; HIV; HIV Entry Inhibitors; HIV Envelope Protein gp120; HIV-1; Heterogeneity; In Vitro; Integration Host Factors; Knowledge; Licensing; Mechanics; Membrane Fusion; Mind; Mutation; Nature; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Plastics; Process; Reagent; Research; Research Personnel; Resistance; Sampling; T-20; Testing; Tropism; Uncertainty; Viral; Virus; Virus Diseases; cell type; design; env Gene Products; experience; fitness; in vitro Assay; in vivo; inhibitor/antagonist; neutralizing antibody; pre-clinical; pressure; programs; receptor expression; resistance mutation; response; tool; virus tropism

DESCRIPTION (provided by applicant): HIV entry inhibitors comprise a new class of antiretroviral drugs that inhibit one of several steps in the virus entry pathway, including CD4-induced conformational changes in gp120, coreceptor binding, and membrane fusion. One membrane fusion inhibitor has been licensed (T20/enfuvirtide), three CCR5 inhibitors will be tested in Phase III clinical trials in 2005, a new CXCR4 inhibitor will soon be used in HIV-infected patients, and several other entry inhibitors are in preclinical and early clinical development. Thus, it can be anticipated that this new class of antiretroviral drugs will assume increasingly greater clinical importance in the years to come. However, the use of entry inhibitors will likely be complicated by the highly variable and plastic nature of the HIV-1 envelope (Env) protein, which results in considerable variability in the sensitivity of virus strains to entry inhibitors, which may result in varied and complex drug resistance pathways some of which could, through alterations in Env, affect virus tropism and pathogenicity. In addition, poorly defined host cell factors have a significant impact on the potency of some entry inhibitors, at least in vitro. Therefore, the primary goals of this R01 proposal are to not only use entry inhibitors as tools to understand Env function, but to use our knowledge of the HIV entry process to better understand how virus and host factors affect entry inhibitor sensitivity, how HIV acquires resistance to entry inhibitors in vivo, and how resistance impacts Env function, sensitivity to other entry inhibitors and neutralizing antibodies. To do this, we will take advantage of a wealth of assays and reagents that we have developed over the past 9 years of this award, as well as collaborations with Dr. Steven Deeks (UCSF) and Joseph Eron (UNC), as the focus of this grant has evolved from studying how HIV enters cells, to how to stop it as effectively as possible. We therefore propose 5 Specific Aims: 1) Define mechanisms by which HIV acquires resistance to T20 in vivo; 2) Define the nature of compensatory mechanisms; 3) Study the effect of entry inhibitor selective pressure on viral tropism; 4) Define the host cell factors that influence entry inhibitor sensitivity; and 5) Characterize resistance to R5 and X4 inhibitors in vitro and in vivo.

描述（由申请人提供）：HIV进入抑制剂包括一类新的抗逆转录病毒药物，这些药物抑制了病毒进入途径的几个步骤之一，包括CD4诱导的GP120构象变化，coreceptor结合和膜融合。一种膜融合抑制剂已获得许可（T20/enfuvirtide），在2005年的III期临床试验中将测试三个CCR5抑制剂，新的CXCR4抑制剂将很快在HIV感染的患者中使用，并且其他一些进入的入口抑制剂在临床和早期临床发育中也是其他入口抑制剂。因此，可以预见的是，这类新的抗逆转录病毒药物将在未来几年中越来越更大。但是，进入抑制剂的使用可能会因HIV-1 Invelope（Env）蛋白的高度可变和可塑性而变得复杂，这会导致病毒菌株对进入抑制剂的敏感性的差异很大，这可能会导致各种且复杂的药物抗性途径，其中一些可能通过Env中的改变，影响病毒型tropism和致病性。此外，定义较差的宿主细胞因子至少在体外对某些进入抑制剂的效力产生了重大影响。因此，该R01提案的主要目标不仅要使用进入抑制剂来理解Env功能，而且还要利用我们对HIV进入过程的了解，以更好地了解病毒和宿主因素如何影响进入抑制剂敏感性，HIV如何获得对体内入口抑制剂的抵抗力，以及抵抗力对ENKINGITION ONKITIVES ENKITIVE，对其他抗抑制剂的敏感性，对其他抑制剂和中性抗体攻击性抑制剂和中性抗体。为此，我们将利用我们在该奖项的过去9年中开发的大量测定和试剂，以及与Steven Deeks（UCSF）和Joseph Eron（UNC）的合作，因为这笔赠款的重点是从研究艾滋病毒进入细胞的方式而发展的，以便如何有效地阻止其有效地阻止它。因此，我们提出了5个具体目的：1）定义艾滋病毒对体内T20的抗性的机制； 2）定义补偿机制的性质； 3）研究进入抑制剂选择性压力对病毒性疗法的影响； 4）定义影响进入抑制剂敏感性的宿主细胞因子； 5）表征体外和体内对R5和X4抑制剂的抗性。