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.

项目概要 全球范围内获得联合抗逆转录病毒疗法 (cART) 已将艾滋病毒感染从死刑变成了绝症 可控制的慢性疾病，其中合并感染和合并症变得越来越重要。在 特别是，HIV-1感染者（PLWH）容易加速/过早衰老 (A/PA) 加剧了非艾滋病发病率和死亡率，通常与社会和经济状况无关。 尽管潜在的罪魁祸首可能包括不健康的生活方式和抗逆转录病毒药物的副作用， 慢性炎症/免疫激活（残留的艾滋病毒复制或微生物易位）和恶化 我们自己的研究发现，免疫健康，包括免疫衰老和免疫衰竭 明确的证据表明，A/PA 是一个高度异质性的结果，因为许多 PLWH 都受到了 1996年之前的基因选择（cART时代的黎明）。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 模糊了 A/PA 的解释。因此，我们的目标是研究免疫遗传学谱和免疫学 可以轻松区分 PLWH 亚组与年龄和性别匹配对照 (HIV-) 受试者的特征 来自一般人群。具体来说，目标 1 将检查生物学和功能上的分布 526 名（342 名 HIV+ 和 184 名 HIV-）青少年和 2,028 名（652 名 HIV+ 和 1,376 名 HIV-）成年人的相关遗传变异， 重点关注单核苷酸多态性 (SNP) 和人类白细胞抗原 (HLA) 变异 已知或预测为 21 种自身免疫性疾病的致病因素，其中包括牛皮癣（一种常见的 炎症性疾病），预计感染者和感染者人数将会增加。来自青少年和成人的基因分型数据 人群（总共 2,554 名受试者）将检验一个中心假设，即表现良好的 PLWH 没有 cART 的人在遗传上是不同的，特别是在保护他们的免疫遗传特征方面 免受艾滋病毒发病机制的影响，同时使他们易患自身免疫性疾病。目标2将进一步检验 按有利和不利遗传分层的感染者青少年和成人的免疫健康轨迹 概况，主要通过分析炎症细胞因子、趋化因子和淋巴细胞的细胞标记物 和单核细胞激活或耗竭。总体而言，这些多学科研究将为 在高度异质性的 PLWH 人群中进行自身免疫和 HIV 相关 A/PA 的转化研究。