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Cellular Reservoirs of HIV

HIV 的细胞库

基本信息

批准号：
10469656
负责人：
Kathleen L. Collins
金额：
$ 65.66万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10469656
关键词：
Anti-Retroviral Agents Biological Assay Biopsy Bone Marrow Aspiration CD4 Positive T Lymphocytes Cells Clonal Expansion Data Epigenetic Process Evolution Frequencies Gene Expression Generations Genetic Transcription Genome HIV HIV Infections HIV-1 Hematopoietic stem cells In Vitro Individual Infection Length Life Modeling Outcome Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Plasma Population Proviruses Public Health Publishing Research Residual state Seeds Site Source Specimen T-Lymphocyte T-Lymphocyte Subsets Testing Tissues United States Viral Viral Genes Viral Genome Viremia Virus Virus Replication antiretroviral therapy base cell type daughter cell drug development in vivo latent infection new therapeutic target pandemic disease peripheral blood progenitor programs reactivation from latency recruit rectal self-renewal stem cell proliferation

项目摘要

Antiretroviral medications suppress viral replication but do not eradicate cellular sources of integrated proviral genomes that are a major barrier to a cure. CD4+ hematopoietic stem and progenitor cells (HSPCs) have the capacity for life-long survival, self-renewal and the generation of daughter cells. They are also susceptible to HIV infection in vitro and in vivo. Combination antiretroviral therapy effectively suppresses viremia in HIV- infected people. However, residual plasma virus (RPV) can be detected with very sensitive assays. Recently published studies demonstrate that clusters of identical proviruses from HSPCs and their likely progeny often match RPV and are sometimes infectious. A higher proportion of these sequences matched RPV than proviral genomes from peripheral blood mononuclear cells that lacked evidence of clonal expansion. Furthermore, we provide examples of proviral genomes from progenitors that were latent in peripheral blood T cells while simultaneously contributing to RPV. The cellular source of RPV in these cases is not known but is unlikely to be peripheral blood T cells, which required latency reactivation for gene expression. We have developed a model based on these data. In this model, we propose that heterogeneous differentiated progeny of infected progenitors can support either active or latent infection depending on progeny epigenetic and transcriptional programs. The overall objective of this application is to test this hypothesis by comprehensively characterizing intact HIV in peripheral blood and tissue reservoirs. A secondary objective is to determine whether infected HSPCs are required for clonal provirus and RPV and to identify any alternative proliferative sources of non- HSPC generated clonal genomes. To accomplish this, we will: 1. Analyze intact near full length viral genomes to identify sources of clonally amplified proviral genomes in peripheral blood and to determine their relationship to proliferative sources such as HSPCs; 2. use viral outgrowth assays to confirm relationships amongst sources of infectious virus; and 3. determine the active and latently infected tissue sources of infectious virus and their relationships to proliferative sources such as HSPCs. Results from these aims will comprehensively identify sources of functional virus and RPV across multiple disparate tissue sites. They will determine the extent to which multipotent and/or restricted progenitors or other proliferative sources serve as the source for clonally expanded HIV proviral genomes present in the peripheral blood and tissue sites. These studies will provide important new information that has the potential to change the way we think about the source of functionally relevant HIV reservoirs.

抗逆转录病毒药物抑制病毒复制，但不能根除整合原病毒的细胞来源