Multidisciplinary Evaluation of Accelerated Aging in HIV-1 Infection

项目摘要 在全球范围内获得抗逆转录病毒联合疗法（cART）已将艾滋病毒感染从死刑判决变成了一种威胁。 可管理的慢性疾病，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）容易遭受加速/过早衰老 （A/PA），加剧了非艾滋病发病率和死亡率，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反应， 慢性炎症/免疫激活（残留的HIV复制或微生物易位）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， 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已经受到了 1996年之前的基因选择（cART时代的黎明）。换句话说， 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 对A/PA的解释。因此，我们的目标是研究免疫遗传学特征和免疫学， 可容易区分PLWH亚组与年龄和性别匹配的对照（HIV-）受试者的特征 从一般人群中。具体来说，目标1将检查生物学和功能性的分布， 526名青年（342名艾滋病毒阳性和184名艾滋病毒阴性）和2 028名成年人（652名艾滋病毒阳性和1 376名艾滋病毒阴性）的相关遗传变异， 重点是单核苷酸多态性（SNP）和人类白细胞抗原（HLA）变异， 已知或预测是21种自身免疫性疾病的致病因素，包括银屑病（一种常见的 炎症性疾病），预计在PLWH人群中会增加。来自青年和成人的基因分型数据 人群（共2，554名受试者）将检验一个中心假设， 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学方面。 从艾滋病毒发病机制，同时诱发他们的自身免疫性疾病。目标2将进一步研究 根据有利和不利遗传因素分层的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标志物， 和单核细胞活化或耗竭。总体而言，这些多学科研究将为以下方面开辟新的途径： 高度异质性PLWH人群中自身免疫和HIV相关A/PA的转化研究。

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.