Role of RhCMV in shaping the SIV proviral landscape

RhCMV 在塑造 SIV 前病毒景观中的作用

• 批准号: 10541869
• 负责人: Joseph Christopher Mudd
• 金额: $ 102.49万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541869
• 关键词: Acceleration; Address; Adoption; Adult; Aftercare; Animal Model; Animals; Antigens; Antiviral Agents; Biological Assay; CD4 Positive T Lymphocytes; Cell Compartmentation; Chronic; Cidofovir; Clonal Expansion; Controlled Study; Cytomegalovirus; DNA; Deuterium; Ensure; Exposure to; FDA approved; Future; Genome; HIV; HIV-1; Herpesviridae; Immunocompetent; Individual; Infection; Inflammatory; Interruption; Intervention; Kinetics; Label; Link; Macaca mulatta; Maintenance; Measurement; Measures; Memory; Modeling; Opportunistic Infections; Patients; Persons; Phenotype; Physiological; Population; Proliferating; Proviruses; Quality of life; Recrudescences; Reporting; Research Personnel; Rest; Rhesus; Role; SIV; Sampling; Shapes; Site; Stimulus; T memory cell; T-Lymphocyte; Time; Tissues; Viral; Virus; aged; antiretroviral therapy; co-infection; cohort; comorbidity; comparative; daughter cell; examination questions; in vivo; insight; integration site; interest; latent HIV reservoir; memory CD4 T lymphocyte; multidisciplinary; nonhuman primate; pathogen; pharmacologic; uptake; viral rebound

Project Summary/Abstract The main obstacle to curing HIV-1 infection is a reservoir that consists of resting memory CD4 T cells whose genomes contain inducible and replication-competent HIV-1 proviruses. Decay of the reservoir is slow and requires lifelong antiretroviral therapy (ART). It has become increasingly clear that the predominant mechanism sustaining HIV-1 persistence during ART is the physiologic proliferation of latent-infected memory CD4 T cells. Infected CD4 T cells can proliferate without producing virus, the result of which will lead to daughter cells harboring expanded HIV-1 proviral clones that share identical sequence and host integration sites. The rate of expansion among distinct proviral clones in this setting however is not equal. In some individuals, upwards of 30% of proviruses sampled can belong to populations that are highly clonally expanded, a mechanism consistent with clonal proliferation by antigen encounter. Establishing a link between particular antigens and the degree to which they independently contribute to HIV persistence, however, is an unresolved question. Cytomegalovirus (CMV) is a latent betaherpesvirus that while asymptomatic in immunocompetent hosts, persistently stimulates the memory T cell pool. Persons living with HIV are near universally coinfected with CMV. In this project, we have assembled a multidisciplinary team of investigators to directly assess the degree to which chronic antigenic stimulation by CMV (i) promotes proliferation of the memory CD4 T cell pool (ii) contributes to clonal diversity and size of the HIV- 1 reservoir during ART and (iii) impacts the time to viral recrudescence when ART is interrupted. Specifically, we will utilize the well-established model of ART-treated SIV-infected rhesus macaques to examine these questions by a dual approach. The first will exploit availability of pathogen-free, rhesus CMV (RhCMV)-naïve rhesus macaques (RMs) to compare SIV reservoir dynamics in the presence or absence of CMV. The second will assess measures of SIV persistence when CMV replication is blocked pharmacologically with antiviral Cidofovir. Critical to our aims are that we will interrogate SIV proviral DNA at multiple longitudinal timepoints, in multiple tissues, and with several assays that inform both quantitative and qualitative aspects of the SIV reservoir. We believe that the comprehensive, highly synergistic, and rigorously controlled studies we propose will (i) identify an immunodominant target that promotes turnover of memory CD4 T cells during ART and by extension, persistence of the HIV-1 reservoir and (ii) provide a rationale to employ recent well-tolerated FDA-approved CMV antivirals as a means to accelerate HIV-1 clearance.

项目摘要/摘要 固化HIV-1感染的主要障碍是一个储层，由静止的记忆CD4 T细胞组成，其基因组 包含诱导和复制能力的HIV-1病毒。水库的衰变很慢，需要终身 抗逆转录病毒疗法（ART）。越来越清楚的是，维持HIV-1持久性的主要机制 在艺术期间，是潜在感染的记忆CD4 T细胞的生理增殖。感染的CD4 T细胞可以增殖 没有产生病毒，其结果将导致具有分享的HIV-1前病毒克隆扩展的子细胞 相同的序列和主机集成位点。但是，在这种情况下，不同的病毒克隆之间的扩张速率是 不相等。在某些人中，已有30％的预科病毒可以属于高度克隆的人群 扩展了，一种与抗原相遇克隆增殖一致的机制。建立特定之间的联系 然而，抗原及其独立促进艾滋病毒持久性的程度是一个尚未解决的问题。 巨细胞病毒（CMV）是一种潜在的β-病毒，虽然在免疫能力宿主中无症状，但持续 刺激内存T细胞池。艾滋病毒感染者几乎与CMV共同感染。在这个项目中，我们 已经组建了一个多学科研究人员，以直接评估慢性抗原刺激的程度 CMV（i）促进了记忆CD4 T细胞池的增殖（II）有助于克隆多样性和HIV的大小 1在艺术期间和（iii）期间的水库会影响艺术中断时的病毒复发时间。具体来说，我们会的 利用经艺术处理的SIV感染的恒河猕猴的良好模型来检查这些问题 方法。第一个将利用无病原体的无病原体CMV（RHCMV）的可用性 - 不含病原体的猕猴（RMS） 在存在或不存在CMV的情况下比较SIV储层动力学。第二个将评估SIV持久性的措施 当CMV复制被抗病毒cidofovir封闭时。对我们的目标至关重要的是我们将 在多个纵向时间点上询问SIV提供DNA，并在多个时间安排中进行询问 SIV储层的定量和定性方面。我们认为，全面，高度协同的和 我们提出的严格控制的研究将（i）确定一个免疫主导目标，以促进记忆的营业额 CD4 T细胞在ART和扩展过程中，HIV-1储层的持久性和（ii）为员工提供了基本原理 经过良好耐受的FDA批准的CMV抗病毒药以加速HIV-1清除率。