T-cell immunity to polyomavirus infection

T细胞对多瘤病毒感染的免疫

• 批准号: 8687581
• 负责人: Aron Eliot Lukacher
• 金额: $ 38.25万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-23 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687581
• 关键词: AIDS/HIV problem; Acute; Affinity; Aging; Animals; Antigens; Antiviral Agents; Antiviral Therapy; Autoimmune Process; BK Virus; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Cycle Kinetics; Cells; Crohn' s disease; Cutaneous; Data; Defect; Demyelinating Diseases; Depressed mood; Disabled Persons; Disease; Dysplasia; Epitopes; Evolution; Flow Cytometry; Functional disorder; Funding; Gene Chips; Gene Silencing; Generations; Genes; Genetic; Genome; Goals; HIV-1; Herpesviridae; Human; Immune; Immunity; Immunocompetent; Immunosuppression; Immunotherapy; Individual; Infection; Inflammation; Inflammatory; JC Virus; Kidney Diseases; Kidney Transplantation; Kinetics; Life; Ligands; Lymphoid; MHC binding peptide; Malignant Neoplasms; Mediating; Memory; Merkel cell carcinoma; Modeling; Molecular; Multiple Sclerosis; Mus; Natural Immunity; Organ; Output; Pathogenesis; Patients; Peptide/MHC Complex; Polyomaviridae; Polyomavirus; Polyomavirus Infections; Population; Progressive Multifocal Leukoencephalopathy; Proteins; Psoriasis; Recruitment Activity; Research; Resistance; Respiratory Tract Infections; Secondary to; Signal Transduction; Skin; Species Specificity; Staging; System; T cell differentiation; T cell response; T memory cell; T-Lymphocyte; Technology; Testing; Transgenic Mice; Transgenic Organisms; Tropism; Variant; Vertebrates; Viral Antigens; Virus; Virus Diseases; Western Blotting; adaptive immunity; effective therapy; handicapping condition; innovation; kidney allograft; lytic replication; mortality; mouse polyomavirus; mutant; novel; parent grant; pathogen; residence; response; retroviral transduction; self-renewal; therapy development; trafficking; tumor; tumorigenesis; virome

DESCRIPTION (provided by applicant): The long-term goal of this renewal application is to understand the mechanisms responsible for generating and maintaining antiviral CD8 T cell responses required to contain persistent "smoldering" viral infections. Persistent virus infections may be categorized into those that are chronically viremic (e.g., HIV-1) and those that maintain themselves by repetitive cycles of reactivation of lytic replication from a noninfectious latent state (e.g., herpesviruses). Polyomaviruses (PyV), silent residents of the "virome" of many vertebrates including humans, persist in a low-level infectious state. However, under conditions of immunosuppression human PyVs can incur life-threatening disease. BK virus is a significant cause of kidney transplant dysfunction and loss. A major cause of mortality in the HIV/AIDS population, JC virus-induced Progressive Multifocal Leukoencephalopathy (PML) has recently emerged in individuals receiving humoral immunotherapies for autoimmune and inflammatory diseases (e.g., multiple sclerosis, Crohn's disease, and severe psoriasis). Several new human PyVs have also recently been isolated from nonbacterial respiratory infections and as a likely causative agent for an aggressive fatal cutaneous malignancy. No effective therapies for PyV infection are available. Due to the tight species specificity of Polyomaviridae that restricts infection to natural animal reservoirs, we have an incomplete understanding of the immune mechanisms needed to keep these smoldering infections in check. Using mouse polyomavirus (MPyV), we discovered that na¿ve virus-specific CD8 T cells are recruited during persistent infection. Data generated in the last funding cycle reveal that temporal differences in recruitment dramatically modulate the quality of the memory T cell compartment. We hypothesize that dynamic changes over the course of infection govern whether MPyV-specific CD8 T cells differentiate into competent memory cells, which, in turn, will be reflected at their levels of gen expression and the TCR-CD8-peptide:MHC tri-molecular interaction. Understanding the mechanisms that control the generation of durable anti-MPyV CD8 T cell memory may help in the development of interventions to enhance immunity to human PyV infections. We will test the above hypothesis in the following three Specific Aims: Aim 1: To define determinants regulating the contribution of acute vs. persistent infection-recruited antiviral CD8 T cells to the memory population. Aim 2: To determine molecular signaling mechanisms underlying the functional differences between acute and persistent infection-recruited MPyV-specific CD8 T cells. Aim 3: To define molecular differences between MPyV-specific memory T cells recruited during acute and persistent infection.

描述（由申请人提供）：本次续期申请的长期目标是了解产生和维持抗病毒CD8 T细胞反应的机制，这些反应是抑制持续“阴燃”病毒感染所必需的。持续性病毒感染