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Novel Mechanisms for Coreceptor Switching

共受体切换的新机制

基本信息

批准号：
8707961
负责人：
DONALD E MOSIER
金额：
$ 23.69万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2013-07-29 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707961
关键词：
Acquired Immunodeficiency Syndrome Address Antiviral Therapy Archives Base Sequence Binding CCR5 gene CD4 Positive T Lymphocytes CXCR4 gene Cell Count Cells Clinical Collaborations Data Disease Drug resistance Event Evolution Exposure to Failure Frequencies Genes Genetic Genetic Recombination HIV-1 Highly Active Antiretroviral Therapy Immune Immune response Immunity Incidence Individual Infection Laboratories Latent virus infection phase Lead Life Longitudinal Studies Mediating Memory Molecular Cloning Mutate Mutation Patients Phenotype Plasma Population Prior Therapy Probability Process Property RNA-Directed DNA Polymerase Recombinants Recording of previous events Research Resistance Rest Retrieval Reverse Transcriptase Inhibitors Sampling Series Staging T memory cell T-Lymphocyte Testing Time Treatment Failure Variant Viremia Virus Work clinical practice cohort env Genes fitness improved information gathering inhibitor/antagonist insight latent infection memory CD4 T lymphocyte non-nucleoside reverse transcriptase inhibitors novel public health relevance reconstitution research study resistance mutation transmission process

项目摘要

DESCRIPTION (provided by applicant): Entry of HIV-1 into target cells is mediated by binding of CD4 and CCR5, but a substantial fraction of infected individuals have sequence changes in the envelope gene that add or replace entry via CCR5 with entry via CXCR4, a process termed "coreceptor switching." The proposed experiments will test several novel hypotheses to explain how coreceptor switching takes place, and why a history of antiviral therapy and low CD4 T cell counts increases coreceptor switching. One hypothesis is that very rapid sequence changes are introduced by recombination events between contemporaneous CCR5 (R5) viruses and CXCR4 (X4) sequences recovered from latently-infected, long-lived memory cells. A competing hypothesis is that bursts of mutation and positive selection drive rapid sequence changes. These will be distinguished by determining the incidence of recombinant envelope genes in entry competent molecular clones from a cohort of 49 patients with documented coreceptor switching events. In those individuals with recombination events that influence coreceptor use, new envelope genes will be cloned by activating the resting memory T cell pool recovered from samples of patient cells stored prior to coreceptor switching. The nucleotide sequences of these genes will be compared to those that contributed to later coreceptor switching to determine if they were the origin of the recombination events. Prior antiviral therapy with reverse transcriptase inhibitors may lead to a higher mutation rate that differently impacts R5 viruses. Neutral, synonymous mutations should accumulate in viruses from subjects with RT inhibitor resistance. Very low CD4 T cell counts leads to a higher proportion of infected cells, which may favor dual infection and recombination. The impact of prior therapy and nadir CD4 T cell counts on events leading to coreceptor switching will be determined by longitudinal studies of virus samples before and after switching. These experiments will lead to a better understanding of how coreceptor switching takes place, and provide new insights into the potential consequences of activating latent infection to eradicate HIV-1.

描述(由申请人提供)：HIV-1进入靶细胞是由CD4和CCR5结合介导的，但相当一部分感染者的包膜基因序列发生变化，通过CCR5增加或取代通过CCR5进入，通过CXCR4进入，这一过程被称为“辅受体转换”。拟议的实验将测试几个新的假设，以解释辅助受体切换是如何发生的，以及为什么抗病毒治疗和低CD4T细胞计数增加辅助受体切换的历史。一种假设是，同时发生的CCR5(R5)病毒与从潜伏感染的长寿命记忆细胞中恢复的CXCR4(X4)序列之间的重组事件导致了非常迅速的序列变化。一个相互竞争的假设是，突变和正向选择的爆发推动了序列的快速变化。通过从49名有记录的辅受体转换事件的队列患者中确定进入能力分子克隆中重组包膜基因的发生率，将这些患者区分开来。在那些具有影响辅受体使用的重组事件的个体中，将通过激活从辅受体转换之前存储的患者细胞样本中恢复的静止记忆T细胞池来克隆新的包膜基因。这些基因的核苷酸序列将与后来辅助受体转换的核苷酸序列进行比较，以确定它们是否是重组事件的起源。之前使用逆转录酶抑制剂进行抗病毒治疗可能会导致更高的变异率，从而对R5病毒产生不同的影响。中性的同义突变应该在RT抑制剂耐药的受试者体内积累。很低的CD4T细胞计数会导致较高比例的感染细胞，这可能有利于双重感染和重组。先前治疗和最低的CD4T细胞计数对导致辅受体转换的事件的影响将通过转换前后的病毒样本的纵向研究来确定。这些实验将有助于更好地理解辅助受体切换是如何发生的，并为激活潜伏感染以根除HIV-1的潜在后果提供新的见解。