Premature T cell aging and vaccine failure in chronic viral infection

慢性病毒感染中 T 细胞过早衰老和疫苗失败

• 批准号: 9023117
• 负责人: Zhi Q. Yao
• 金额: --
• 依托单位: JAMES H QUILLEN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9023117
• 关键词: 5' -exoribonuclease; Accounting; Affect; Age; Aging; Antigens; B-Lymphocytes; Biological Markers; CD4 Positive T Lymphocytes; Cell Aging; Cell physiology; Cessation of life; Chronic; Chronic Hepatitis C; Coculture Techniques; Elderly; Epidemic; Exhibits; Failure; Functional disorder; Gene Targeting; Goals; HIV; HIV Infections; Health; Hemodialysis; Hepatitis B Vaccination; Hepatitis B Vaccines; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Immune; Immune response; Immunization; Immunocompromised Host; Impairment; Individual; Infection; Interleukin-10; Interleukin-2; Killer Cells; Lectin; Mediating; MicroRNAs; Modeling; Morbidity - disease rate; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Population; Proteins; Receptor Activation; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Risk Factors; Role; Signal Transduction; Signaling Molecule; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Transforming Growth Factor beta; Translations; United States; Up-Regulation; Vaccination; Vaccines; Veterans; Virus; Virus Diseases; Work; aged; base; cancer transplantation; cell age; chronic liver disease; clinically significant; co-infection; cohort; cost; exhaustion; improved; member; mortality; overexpression; premature; prevent; public health relevance; receptor; reconstitution; response; senescence; seroconversion; translational study; vaccine efficacy; vaccine response

 DESCRIPTION (provided by applicant) The overall goal of this proposal is to elucidate the mechanisms by which chronic viral infection mediates premature T cell aging and vaccine failure through regulation of microRNA-regulated proteins, with an aim to develop effective approaches to improve vaccine efficacy in virus-infected individuals. To this end, we will use a model of hepatitis B virus (HBV) vaccine failure i the setting of chronic hepatitis C virus (HCV) infection. The proposal is based on the fact that co-infection of HBV with HCV is common due to shared risk factors, and as such HBV vaccine is required to prevent super-infection and its associated increase in morbidity and mortality; however, vaccine responses in virus-infected individuals are often blunted. This phenomenon is also observed in the elderly who frequently fail to respond to vaccinations; and attempts to improve the rate of immunizations in both infected and aged populations have been unsuccessful, in part due to our poor understanding of the mechanisms that inhibit vaccine responses in these settings. In studying the effect of chronic viral infection on T cell functions, we and others have recently found that chronic HCV infection leads to T cell dysfunction mediated through up-regulation of aging markers, including killer cell lectin-like receptor subfamily G member 1 (KLRG1) and dual specific phosphatase 6 (DUSP6), concomitant with a decline of microRNA-155 (miR155) levels in CD4 T cells. Remarkably, these alterations are associated with impaired CD4 T cell functions in HCV- infected individuals and are more prominent in HBV vaccine non-responders (HBV-NR) compared to age- matched HBV vaccine responders (HBV-R). It has been demonstrated that with increasing age, KLRG1 is up- regulated and leads to inhibition of T cell receptor (TCR) signaling; whereas DUSP6 is increased and leads to recalibration of the TCR activation threshold; and miR155 decline is known to permit translation of a set of target genes related to T cell inhibition. However, the mechanisms underlying miR155/KLRG1/DUSP6 expression and regulation of premature T cell aging and vaccine responses during HCV infection remain unknown. In this proposal, we hypothesize that HCV-induced loss of miR155 mediates premature T cell aging by up-regulating KLRG1 and/or DUSP6 expressions, such that targeting these inhibitory pathways may rescue impaired CD4 T cell functions and subsequently boost blunted vaccine responses in virus-infected individuals. To test this hypothesis, we will carry out the following two specific aims: Aim 1 will define the transcriptional and translational mechanisms that control miR155 expression and the role of miR155 in regulating KLRG1 and/or DUSP6 expression in T cells during HCV infection; Aim 2 will examine the consequences of miR155 loss and KLRG1/DUSP6 over-expression in T cell function and vaccine response in virus-infected individuals. This translational study is significant in that it provides a working model to explore mechanisms that may be fundamental to diminished vaccine responses in general, particularly in the setting of immunocompromise by HIV, hemodialysis, transplantation, and cancer.