Multidisciplinary Evaluation of Accelerated Aging in HIV-1 Infection

项目总结 全球获得联合抗逆转录病毒疗法(CART)已将艾滋病毒感染从死刑转变为 可控制的慢性疾病，在这种疾病中，合并感染和共病变得越来越重要。在……里面 特别是，艾滋病毒-1感染者(PLWH)容易遭受加速/过早衰老的痛苦。 (A/PA)，这加剧了非艾滋病的发病率和死亡率，往往与社会和经济地位无关。 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不良影响 慢性炎症/免疫激活(残留的艾滋病毒复制或微生物移位)和 免疫健康，包括免疫衰老和免疫衰竭，我们自己的研究发现 清楚的证据表明，A/PA是一个高度不同的结果，因为许多PLWH都经历了 1996年前的遗传选择(CART时代的曙光)。换句话说，可遗传的遗传因素 以不同方式调节新陈代谢、感染、免疫和免疫病理(例如自身免疫性疾病)可以 模糊了对A/PA的解释。因此，我们的目标是研究免疫遗传图谱和免疫学 容易区分PLWH亚组与年龄和性别匹配的对照(HIV-)受试者的特征 从普通人群中分离出来。具体地说，目标1将检查生物和功能上的分布 526名青年(342名艾滋病毒携带者和184名艾滋病毒携带者)和2028名成年人(652名艾滋病毒携带者和1376名艾滋病毒携带者)的相关基因变异， 重点关注单核苷酸多态(SNPs)和人类白细胞抗原(HLA)变种 已知或预测是21种自身免疫性疾病的致病因素，包括牛皮癣(一种常见的 炎症性疾病)，预计在PLWH人群中将上升。青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，即成功取得良好成绩的PLWH 没有CART的人在基因上是不同的，特别是在保护他们的免疫遗传特征方面 从艾滋病毒的发病机制，同时使他们容易患上自身免疫性疾病。Aim 2将进一步检查 按有利和不利基因分层的PLWH青年和成人的免疫健康轨迹 主要通过分析炎性细胞因子、趋化因子和淋巴细胞的细胞标记物 单核细胞激活或耗尽。总体而言，这些多学科研究将开辟新的途径 高度异质性PLWH人群自身免疫和HIV相关A/PA的翻译研究

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.