Multidisciplinary Evaluation of Accelerated Aging in HIV-1 Infection

HIV-1 感染加速衰老的多学科评估

• 批准号: 9271038
• 负责人: Jianming Tang
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271038
• 关键词: Acquired Immunodeficiency Syndrome; Adult; Adverse effects; Age; Aging; Alleles; Anti-Retroviral Agents; Applications Grants; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Biological Assay; C-reactive protein; CCL2 gene; CD28 gene; Cells; Cessation of life; Characteristics; Chronic; Chronic Disease; Chronology; Clinical; Comorbidity; Cytotoxic T-Lymphocyte-Associated Protein 4; Data; Data Analyses; Data Set; Deterioration; Disease; Drug toxicity; Economics; Elderly; Enzyme-Linked Immunosorbent Assay; Epidemic; Evaluation; Flow Cytometry; Gender; General Population; Genetic; Genetic Drift; Genomics; Genotype; Goals; HIV; HIV Infections; HIV-1; HLA Antigens; Heritability; Heterogeneity; Immune; Immunity; Immunogenetics; Immunologic Markers; Immunologics; Immunology; Immunosuppressive Agents; Individual; Infection; Inflammation; Inflammatory; Interleukin-18; Intervention; Life Style; Long-Term Effects; Lymphocyte; Mediating; Metabolism; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; Organ; Outcome; Pathogenesis; Pattern; Peripheral; Persons; Plasma; Population; Premature aging syndrome; Psoriasis; RANTES; Recording of previous events; Regimen; Research; Residual state; Sampling; Single Nucleotide Polymorphism; Smoking; Subgroup; Substance abuse problem; Survivors; Testing; The Multicenter AIDS Cohort Study; Time; Translational Research; Variant; Virus; Visit; Woman; Women’s Interagency HIV Study; Youth; age group; antiretroviral therapy; chemokine; co-infection; cohort; cytokine; demographics; design; exhaustion; follow-up; fundamental research; genetic profiling; genetic selection; genetic variant; genome wide association study; human genomics; immune activation; immune health; immunopathology; immunosenescence; indexing; men; microbial; middle age; monocyte; mortality; multidisciplinary; senescence; social; success; tool; unhealthy lifestyle

PROJECT SUMMARY Global access to combination antiretroviral therapy (cART) has turned HIV infection from a death sentence to a manageable, chronic illness in which co-infections and comorbidities become increasingly important. In particular, persons living with HIV-1 infection (PLWH) are prone to suffering from accelerated/premature aging (A/PA) that exacerbates non-AIDS morbidity and mortality, often regardless of social and economic status. Although the potential culprits can range from unhealthy lifestyle and adverse effects of antiretrovirals to chronic inflammation/immune activation (residual HIV replication or microbial translocation) and deterioration of immunologic health, including immune senescence and immune exhaustion, our own research has uncovered clear evidence that A/PA is a highly heterogeneous outcome because many PLWH have been subjected to a genetic selection before 1996 (the dawn of cART era). In other words, heritable genetic factors that differentially mediate metabolism, infection, immunity, and immunopathology (e.g., autoimmune disorders) can obscure the interpretation of A/PA. Accordingly, we aim to study immunogenetic profiles and immunologic features that may readily distinguish PLWH subgroups from age- and gender-matched control (HIV-) subjects from the general population. Specifically, Aim 1 will examine the distribution of biologically and functionally relevant genetic variants in 526 (342 HIV+ and 184 HIV-) youth and 2,028 (652 HIV+ and 1,376 HIV-) adults, with a focus on single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) variants that are known or predicted to be causal factors for 21 autoimmune conditions, including psoriasis (a common inflammatory disease) that is expected to rise in PLWH populations. Genotyping data from youth and adult populations (2,554 total subjects) will test a central hypothesis that PLWH who managed to do well without cART are genetically distinct, especially in terms of immunogenetic profiles that protect them from HIV pathogenesis, while predisposing them to autoimmune disorders. Aim 2 will further examine trajectories of immunologic health in PLWH youth and adults stratified by favorable and unfavorable genetic profiles, primarily through analyses of inflammatory cytokines, chemokines, and cellular markers of lymphocyte and monocyte activation or exhaustion. Overall, these multidisciplinary studies will open new avenues for translational research on autoimmunity and HIV-related A/PA in the highly heterogeneous PLWH populations.

项目摘要 全球获得抗逆转录病毒疗法（CART）的联合通道已将艾滋病毒感染从死刑变成 可管理的慢性疾病，共同感染和合并症变得越来越重要。在 特别是，患有HIV-1感染（PLWH）的人容易患有加速/过早衰老 （A/PA）加剧非辅助的发病率和死亡率，无论社会和经济状况如何。 尽管潜在的罪魁祸首可能从抗逆转录病毒的不健康生活方式和不良影响到 慢性炎症/免疫激活（残留的HIV复制或微生物易位）和恶化 免疫健康，包括免疫衰老和免疫疲劳，我们自己的研究已经揭露 明确的证据表明A/PA是高度异构结果，因为许多PLWH已受到 1996年之前的遗传选择（购物车时代的曙光）。换句话说，可遗传的遗传因素 差异介导代谢，感染，免疫和免疫病理学（例如自身免疫性疾病）可以 掩盖A/PA的解释。因此，我们旨在研究免疫发明特征和免疫学 可能很容易区分PLWH子组与年龄和性别匹配的对照（HIV-）受试者的功能 来自普通人群。具体而言，AIM 1将检查生物学和功能的分布 526（342 HIV+和184 HIV-）青年和2,028（652 HIV+和1,376 HIV-）成年人的相关遗传变异 关注单核苷酸多态性（SNP）和人类白细胞抗原（HLA）变体 已知或预测是21种自身免疫性疾病的因果因素，包括牛皮癣（一种常见 炎症性疾病）预计PLWH人群将增加。来自青年和成人的基因分型数据 人群（2,554名受试者）将检验一个中心假设，即设法做得很好的PLWH 没有卡车在遗传上是不同的，尤其是在保护它们的免疫遗传特征方面 从HIV发病机理中，同时使其易于自身免疫性疾病。 AIM 2将进一步检查 PLWH青年和成人的免疫健康轨迹通过有利和不利的遗传分层 剖面，主要通过分析淋巴细胞的炎性细胞因子，趋化因子和细胞标记物 和单核细胞激活或精疲力尽。总体而言，这些多学科研究将为 在高度异质的PLWH种群中，关于自身免疫性和与HIV相关的A/PA的转化研究。