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Persistent HIV expression induced type I IFN responses and inflammaging

持续的 HIV 表达诱导 I 型 IFN 反应和炎症

基本信息

批准号：
10396622
负责人：
SURYARAM GUMMULURU
金额：
$ 77.17万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10396622
关键词：
Adverse effects Age Aging Atherosclerosis Autologous Automobile Driving Biological Biopsy CD8-Positive T-Lymphocytes CD8B1 gene Cardiovascular Diseases Cardiovascular system Cells Chronic Clinical Coculture Techniques DNA Defect Development Disease Elderly Exhibits Fc Receptor Gene Expression Genetic Transcription HIV HIV Infections Immune Immunologics In Vitro Individual Inflammaging Inflammation Inflammation Mediators Inflammatory Inflammatory Response Innate Immune Response Interferons Intervention Link Longitudinal Studies Macrophage Activation Malignant Neoplasms Measurement Mediating Mitochondria Modeling Morbidity - disease rate Myeloid Cells Neurocognitive Deficit Neurologic Older Population Osteoporosis Pathogenesis Peripheral Blood Mononuclear Cell Process Production Prospective cohort RNA Receptor Cell Residual state Risk Sampling Secondary to Signal Transduction Signaling Protein Stimulus Suggestion Testing Tissues Viral Viral reservoir Viremia Virion Virus Virus Inhibitors age related aged aging population antagonist antiretroviral therapy cytokine effector T cell exhaustion experimental study follow-up functional disability high risk immune activation in vivo innate immune sensing innovation insight macrophage monocyte mortality prevent receptor receptor expression response success viral RNA

项目摘要

ABSTRACT Despite effective anti-retroviral therapy (cART), HIV-infected individuals remain at an unusually high risk of morbidity and mortality from HIV-associated non-AIDS (HANA) clinical conditions, such as cardiovascular disease, neurocognitive decline, and osteoporosis. The excess risk for these age-related diseases is attributed to the residual immune activation that persists despite cART. Older cART-suppressed HIV-infected individuals have an even greater risk for these inflammation-driven diseases compared to younger counterparts;; this suggests a synergistic adverse effect of HIV and advanced age. In our preliminary studies, we observed that cART-suppressed HIV+ individuals, especially those of older age (≥50), exhibited higher monocyte/macrophage activation and had greater cell-associated RNA levels (ca-RNA) despite no significant difference in reservoir size (HIV DNA), suggesting a link between HIV gene expression and monocyte activation. Importantly, we found that de novo HIV unspliced viral RNA expression alone, even in the absence of virus particle production, can induce production of type I IFN responses and pro-inflammatory cytokines in macrophages. In addition, we observed that HIV and aging appear to synergistically advance CD8+ T cell exhaustion, as defined by increased expression of inhibitory receptors (IRs). Also, co-culture of HIV-infected macrophages and CD8+ T cells revealed that increased IR expression is mediated, at least in part, by type I IFNs. Collectively, these preliminary findings support our central hypothesis that the increased HIV unspliced RNA expression in aged individuals drives type I IFN responses from infected monocytes/macrophages, which in turn promotes CD8+ T cell exhaustion, causing a loss of virological control, and hence, perpetuating this HANA-inducing inflammatory cycle. In this study, we propose innovative approaches and sampling from a prospective cohort of HIV-infected individuals stratified by age and matched by duration of cART compared to age-matched uninfected individuals to test our hypothesis. In Aim 1 we will determine if expression of unspliced HIV RNA in macrophages and ageing synergistically enhance type I IFN responses. In Aim 2 we will determine how age, HIV, and monocyte/macrophage-derived inflammatory responses drive CD8+ T cell exhaustion. In Aim 3 we will evaluate how age and CD8+ T cell exhaustion contribute to the persistence and expression of the viral reservoir. We predict that these studies will lead to the identification of the biological mechanisms that drive HANA diseases despite effective cART. Such insight will be critically important for development of effective strategies to decrease or reverse the persistent immune activation driving disease pathogenesis in the growing population of older (≥50 years old) individuals living with HIV.

文摘