The push and pull of inflammation on HIV susceptibility: impact of host variation in CD101 and AXL

炎症对 HIV 易感性的推拉：CD101 和 AXL 宿主变异的影响

基本信息

批准号：
10664009
负责人：
Florian Hladik
金额：
$ 79.96万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-12 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10664009
关键词：
Accounting Africa African Archives Autophagocytosis Biological Biological Specimen Banks Blood Blood Cells CD8-Positive T-Lymphocytes Cell Nucleus Cells Colitis Counseling Cryopreservation Data Diabetes Mellitus Disease Epidemiology Equilibrium Exhibits Exposure to Genes Genetic Genital Genitalia Genome Genotype HIV HIV risk HIV-1 Heterosexuals Highly Active Antiretroviral Therapy Homeostasis Immune Immunoglobulin Domain Immunologics In Vitro Individual Infection Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune Response Interferons Interleukin-2 Intervention Knowledge Link Macrophage Mediating Medicine Membrane Molecular Mucous Membrane Mus Myeloid Cells Natural Resistance Nuclear Translocation Outcome Pathway interactions Peripheral Blood Mononuclear Cell Persons Phenotype Population Predisposition Prevention approach Production Public Health RNA Splicing Receptor Protein-Tyrosine Kinases Regulation Regulatory T-Lymphocyte Reporting Research Personnel Resistance Risk Sampling Single Nucleotide Polymorphism Site T-Cell Activation T-Lymphocyte Techniques Testing Tissues Toll-like receptors Tyrosine Kinase Receptor Inhibition United States Untranslated Regions Variant Viral Woman base editing cell type chemokine cohort cytokine ethnic diversity female sex worker genetic variant genital infection genome editing genomic data hazard high risk high risk men immune activation infection risk men who have sex with men monocyte novel novel strategies nuclear factors of activated T-cells pandemic disease pathogen pre-exposure prophylaxis prevent protective allele recruit risk variant sample archive seroconversion trait transcription factor transcriptome vaginal mucosa

项目摘要

ABSTRACT Despite the significant public health impact of highly active antiretroviral therapy and pre-exposure prophylaxis on the HIV-1 pandemic, fundamental questions remain about the biological mechanisms that define the risk of sexually acquiring HIV-1. Notably, there is no explanation why, after accounting for genetic variants that directly modify HIV-1 entry and replication (foremost CCR5Δ-32), individuals with documented high exposure to HIV- 1 exhibit diverse outcomes ranging from rapid infection to prolonged natural resistance to HIV-1 infection. A better understanding of these phenotypes could lead to novel interventions to reduce HIV-1 acquisition. We previously identified functional variants (missense/nonsense, untranslated region, or splice site) in host genes that are strongly associated with altered risk of heterosexually acquired HIV-1 infection. Notably, genetic variants in CD101 had the strongest association with increased HIV-1 risk, while variants in AXL had substantially reduced risk. Both genes are thought to regulate host inflammatory responses. CD101 regulates T cell activation and is expressed on many immune cell types. We recently reported that circulating T cells and monocytes from donors with these CD101 variants, compared to donors without functional CD101 variants, show higher overall cellular activation, but with reduced expression of certain HIV-protective interferon stimulated genes. In contrast, AXL is a receptor tyrosine kinase thought to act through myeloid cells to inhibit cellular immune activation, possibly through inhibition of toll-like receptor-mediated innate immune responses. Our overarching hypothesis is that host variation in CD101 and AXL genotypes contributes to altered inflammatory homeostasis, thereby influencing the risk of HIV-1 infection. Specifically, we hypothesize that CD101 variants confer a higher risk of HIV-1 infection by increasing the abundance and activation of HIV-1 susceptible T cells, while also compromising their innate antiviral defenses. Conversely, the absence of these variants, possibly augmented by reduced inflammation conferred by AXL variants, lowers HIV-1 infection risk. We propose to evaluate our hypothesis in three aims: in Aim 1, we use genomic data from a cohort with well- characterized HIV-1 acquisition phenotypes to replicate in a second high HIV-risk African cohort that AXL variants balance the impact of CD101 variants on HIV-1 susceptibility. In Aim 2, we test the epidemiological and population generalizability of our hypothesis by quantifying the association of CD101 and AXL variation with susceptibility to HIV-1 infection in two US populations for which genomic data already exist: one that includes predominantly white men who have sex with men; and a second, ethnically diverse cohort recruited across the entire US. In Aim 3, we apply molecular techniques to blood and genital mucosal samples archived in a unique biospecimen repository to directly link the presence of these CD101 and AXL variants with host inflammatory mechanisms, and ex vivo HIV-1 susceptibility.

抽象的尽管高度活跃的抗逆转录病毒疗法和暴露前预防对公共卫生产生重大影响在HIV-1大流行中，关于定义的生物学机制仍然存在的基本问题性获取HIV-1。值得注意的是，没有任何解释，为什么在考虑了直接的遗传变异之后修改HIV-1输入和复制（FormostCCR5δ-32），具有高暴露于HIV-的个人 1展示了从快速感染到长时间自然抵抗到HIV-1的潜水员结局感染。更好地了解这些表型可能会导致新的干预措施减少HIV-1 获得。我们先前鉴定了功能变体（错义/胡说八道，未翻译区域或剪接位点）在宿主基因中与异性偶发性获得HIV-1感染的风险改变密切相关的宿主基因。尤其， CD101中的遗传变异与HIV-1风险的增加相关，而AXL中的变异风险大大降低。两种基因都被认为调节宿主炎症反应。 CD101 调节T细胞活化，并在许多免疫细胞类型上表达。我们最近报道了循环t 与没有功能性CD101的供体相比变体显示较高的总体细胞激活，但由于某些HIV保护干扰素的表达降低刺激基因。相比之下，AXL是一种被认为通过髓样细胞起作用的受体酪氨酸激酶以抑制细胞免疫激活，通过抑制Toll样受体介导的先天免疫调查剂，可能。我们的总体假设是CD101和AXL基因型中的宿主变异有助于改变炎症稳态，从而影响HIV-1感染的风险。具体来说，我们假设 CD101变体会议通过增加HIV-1的丰度和激活而较高的HIV-1感染风险易感T细胞，同时也损害了其先天的抗病毒防御能力。相反，缺乏这些 AXL变体降低的感染可能增强的变体降低了HIV-1感染风险。我们建议在三个目标中评估我们的假设：在AIM 1中，我们使用来自具有良好良好队列的基因组数据表征了HIV-1采集表型以在第二个高艾滋病风险的非洲同类中复制AXL变体平衡CD101变体对HIV-1易感性的影响。在AIM 2中，我们测试流行病学和通过量化CD101和AXL变化与已经存在基因组数据的两个美国人群中HIV-1感染的敏感性：一个包括主要是白人与男人发生性关系的白人；第二次，种族多元化的队列在整个人群中招募在AIM 3中，我们将分子技术应用于血液和生殖器粘膜样品，以独特的生物测量存储库直接将这些CD101和AXL变体的存在与宿主炎症联系起来机制和离体HIV-1敏感性。