Long-term consequences of HIV in the Kidney

艾滋病毒对肾脏的长期影响

• 批准号: 10155087
• 负责人: John Cijiang He
• 金额: $ 183.26万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155087
• 关键词: AIDS-Associated Nephropathy; APOL1 gene; Acetylation; Address; Affect; African; African American; Aging; Animal Model; Attenuated; Biopsy; Bromodomain; Cell model; Cells; Chronic; Chronic Disease; Chronic Kidney Failure; Collaborations; Common Core; Communication; Consequences of HIV; Data; Data Set; Dendritic Cells; Diabetes Mellitus; Disease; End stage renal failure; Engineering; Epidemiology; Epigenetic Process; Epithelial Cells; Event; Focal Segmental Glomerulosclerosis; Funding; Gene Expression; Gene Expression Profile; General Population; Grant; HIV; HIV Infections; Health; Histopathology; House mice; Human; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Informatics; Integration Host Factors; Intervention; Kidney; Kidney Diseases; Life Cycle Stages; Link; Mediating; Morbidity - disease rate; NF-kappa B; Natural History; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Population; Program Research Project Grants; Publishing; Recording of previous events; Renal tubule structure; Reporting; Research; Research Personnel; Resources; Risk; Role; SIRT1 gene; STAT3 gene; Sampling; Science; Single Nucleotide Polymorphism; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor-infiltrating immune cells; Variant; Viral; Viral reservoir; Virus; Work; acute infection; aging population; antiretroviral therapy; cell injury; chronic infection; comorbidity; data sharing; disorder risk; germ free condition; gut microbiota; host microbiome; immune activation; improved; in vivo; inhibitor/antagonist; innovation; insight; kidney cell; knock-down; macrophage; mortality; mouse model; multidisciplinary; multimodality; overexpression; podocyte; programs; receptor; renal epithelium; risk variant; synergism; systemic inflammatory response; therapeutic target; unpublished works

Summary (OVERALL) The introduction of antiretroviral therapy (ART) in the mid-1990's has had a dramatic impact on the natural history of HIV infection and HIV-associated nephropathy (HIVAN). While the overall mortality and the incidence of ESRD attributed to HIVAN has decreased, the incidence of all cause ESRD among HIV-infected patients has not changed and remains significantly higher than that observed in the general population. With prolonged survival and aging of the HIV population, non-AIDS complications including kidney disease have emerged as major contributors to morbidity and mortality and continue to disproportionately affect individuals of African origin. The latter can at least partially be explained by the strong association of single nucleotide polymorphisms (SNP) in APOL1 with idiopathic and HIV-associated FSGS in African- Americans, although the mechanism remains unknown. This Program Project Grant will investigate the long-term consequences of chronic HIV infection on the kidney including contribution to chronic kidney disease, critical host factors that influence that interaction as well as the role the kidney plays as a long-term, potentially latent reservoir for the virus that could drive chronic inflammation. Critical observations made in the prior funding cycle have contributed to the work proposed including the observation that HIV infection accelerates the progression of kidney disease in the setting of diabetes and that HIV completes a virus life cycle in the kidney, induces inflammation and in the kidney and can become latent in a subset of renal tubule epithelial cells. Key Inflammatory pathways induced by HIV have been defined in renal tubule epithelial cells and in podocytes providing insights for possible interventions that will be explored. New preliminary data in the HIV transgenic murine model has demonstrated an interaction between host microbiome and kidney pathogenesis. Through three highly interactive projects (and two linked RO-1s) and four essential cores, with investigators that have a strong track record of collaboration, we will explore the hypothesis that chronic infection with HIV, even under complete viral suppression, has long-term consequences in the kidney, both by promoting CKD (Project 4) and by providing a long-term reservoir for the virus that promotes chronic inflammation (Project 2 and linked RO-1) and that critical host factors influence these consequences including APOL1 variants (linked RO-1) and host microbiome (Project 3). Engineered transformed and primary cells, transgenic murine models and human samples provided by Core C with biopsy histopathology determined by the histopathology Core (B) will be used to explore the hypotheses proposed. An informatics Core (D) will provide critical and innovative analyses of in vitro and in vivo derived data sets. A multi-modality communications and data sharing plan will allow continuous review of data and sharing of experimental approaches and data to move the science forward. This PPG addresses important challenges in HIV and CKD research, including the intersection of HIV and progression of chronic diseases associated with aging, as well as the recognition that cure initiatives require a complete understanding of the implications of HIV in chronic reservoirs.

摘要（总体） 20世纪90年代中期抗逆转录病毒疗法（ART）的引入对自然疗法产生了巨大影响。 HIV 感染史和 HIV 相关肾病 (HIVAN) 史。虽然总死亡率和发病率 归因于 HIVAN 的 ESRD 有所下降，HIV 感染者中全因 ESRD 的发生率 没有改变，并且仍然显着高于一般人群中观察到的水平。随着时间的延长 随着艾滋病毒人口的生存和老龄化，包括肾病在内的非艾滋病并发症已成为 发病率和死亡率的主要原因，并继续对非洲人产生不成比例的影响 起源。后者至少可以部分地通过单核苷酸的强关联来解释 APOL1 的多态性 (SNP) 与非裔美国人中特发性和 HIV 相关的 FSGS 相关，尽管 机制仍不清楚。该计划项目拨款将调查以下问题的长期后果： 肾脏的慢性艾滋病毒感染，包括导致慢性肾病的关键宿主因素 影响这种相互作用以及肾脏作为长期、潜在的潜在储存库的作用 可能导致慢性炎症的病毒。上一个资助周期中提出的批评意见 对拟议的工作做出了贡献，包括观察到艾滋病毒感染加速了进展 糖尿病背景下的肾脏疾病以及艾滋病毒在肾脏中完成病毒生命周期，诱导 炎症和肾脏中的炎症，并且可以潜伏在肾小管上皮细胞的一部分中。钥匙 HIV 诱导的炎症途径已在肾小管上皮细胞和足细胞中得到确定 为将要探索的可能干预措施提供见解。 HIV转基因的新初步数据 小鼠模型已证明宿主微生物组与肾脏发病机制之间存在相互作用。通过 三个高度互动的项目（以及两个相关的 RO-1）和四个基本核心，研究人员拥有 良好的合作记录，我们将探讨这样一个假设：慢性感染艾滋病毒，即使在 完全抑制病毒，通过促进 CKD（项目 4）和 通过为促进慢性炎症的病毒提供长期储存库（项目 2 和相关 RO-1） 影响这些后果的关键宿主因素包括 APOL1 变体（连接 RO-1）和宿主 微生物组（项目 3）。工程转化细胞和原代细胞、转基因小鼠模型和人类 由核心 C 提供的样本，并由组织病理学核心 (B) 确定活检组织病理学 用于探索所提出的假设。信息学核心 (D) 将提供批判性和创新性分析 体外和体内衍生的数据集。多模态通信和数据共享计划将允许 不断审查数据并共享实验方法和数据，以推动科学向前发展。 该 PPG 解决了 HIV 和 CKD 研究中的重要挑战，包括 HIV 和 CKD 的交叉点 与衰老相关的慢性疾病的进展，以及认识到治疗举措需要 完全了解艾滋病毒对慢性储存者的影响。

项目成果

Induction of retinol dehydrogenase 9 expression in podocytes attenuates kidney injury.

足细胞中视黄醇脱氢酶 9 表达的诱导可减轻肾损伤。

• DOI: 10.1681/asn.2013111150
• 发表时间: 2014-09-01
• 期刊: Journal of the American Society of Nephrology : JASN
• 作者: Xuezhu Li;Yan Dai;Peter Y. Chuang;J. He
• 通讯作者: J. He

Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected versus uninfected adults.

HIV感染者与未感染者的心肌梗死、终末期肾病和非艾滋病定义癌症的风险和诊断年龄的比较。

• DOI: 10.1093/cid/ciu869
• 发表时间: 2015-02-15
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: K. Althoff;K. McGinnis;C. Wyatt;M. Freiberg;C. Gilbert;K. Oursler;D. Riml;M. Rodriguez‐Barradas;R. Dubrow;L. Park;M. Sk;erson;erson;M. Shiels;S. Gange;K. Gebo;A. Justice
• 通讯作者: A. Justice

The spectrum of kidney biopsy findings in HIV-infected patients in the modern era.

现代艾滋病毒感染者的肾活检结果的范围。

• DOI: 10.1016/j.kint.2020.01.018
• 发表时间: 2020-02-04
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Satoru Kudose;D. Santoriello;A. Bomback;M. Stokes;I. Batal;G. Markowitz;C. Wyatt;V. D’Agati
• 通讯作者: V. D’Agati

Chronic kidney disease in a murine model of non-alcoholic steatohepatitis (NASH).

非酒精性脂肪性肝炎（NASH）小鼠模型中的慢性肾病。

• DOI: 10.1016/j.kint.2023.12.009
• 发表时间: 2023-12-01
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Xuezhu Li;Dipankar Bhattacharya;Yue Yuan;Chengguo Wei;Fang Zhong;Feng Ding;Vivette D. D’Agati;Kyung Lee;Scott L. Friedman;J. He
• 通讯作者: J. He

Pharmacotherapeutic options for kidney disease in HIV positive patients.

HIV 阳性患者肾脏疾病的药物治疗选择。

• 发表时间: 2021-01
• 影响因子: 3.2
• 作者: Tariq, Anam;Kim, Hannah;Abbas, Hashim;Lucas, Gregory M;Atta, Mohamed G
• 通讯作者: Atta, Mohamed G