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）：将HIV-1进入靶细胞的进入是通过CD4和CCR5的结合介导的，但是很大一部分受感染的个体在包膜基因中具有序列变化，该序列变化是通过CXCR4通过CXCR4添加或替换CCR5的序列变化，该过程称为“ Coreceptor Switching”。提出的实验将检验几种新型假设，以解释如何发生共感受器的转换，以及为什么抗病毒药疗法和低CD4 T细胞计数的史增加了共受体转换。一个假设是，从同时性CCR5（R5）病毒与CXCR4（X4）序列之间的重组事件引入了非常快速的序列变化，这些事件是从潜在感染的，长期寿命的记忆细胞中恢复的。一个竞争的假设是突变和阳性选择的爆发驱动快速序列变化。这些将通过确定来自49例有记录的共感受器切换事件的患者的队列中的重组包膜基因的发生率来区分。在那些会影响使用共受体使用的重组事件的个体中，将通过激活从colecector转换之前存储的患者细胞样品中恢复的静息记忆T细胞池克隆新的包膜基因。这些基因的核苷酸序列将与有助于后来的共核能切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。先前使用逆转录酶抑制剂的抗病毒治疗可能导致更高的突变率，从而影响R5病毒。中性的，同义突变应在病毒中积累来自RT抑制剂耐药性的受试者。 CD4 T细胞计数非常低导致更高比例的感染细胞，这可能有利于双重感染和重组。先前的疗法和Nadir CD4 T细胞计数对导致共感受器转换的事件的影响将由切换前后病毒样本的纵向研究确定。这些实验将使人们更好地理解对共受体转换的发生，并提供新的见解，以了解激活潜在感染以消除HIV-1的潜在后果。