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

• 批准号: 10546199
• 负责人: Florian Hladik
• 金额: $ 81.52万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 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/10546199
• 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; Lead; Link; Mediating; Medicine; 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; United States; Untranslated Regions; Variant; Woman; base; base editing; cell type; chemokine; cohort; cytokine; density; ethnic diversity; female sex worker; genetic variant; genital infection; genome editing; genomic data; hazard; high risk; high risk men; immune activation; infection risk; macrophage; men who have sex with men; monocyte; novel; novel strategies; nuclear factors of activated T-cells; pandemic disease; pathogen; pre-exposure prophylaxis; prevent; programs; protective allele; recruit; risk variant; sample archive; trait; transcription factor; transcriptome; vaginal mucosa

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.

摘要 尽管高效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， 关于HIV-1大流行，关于定义感染风险的生物学机制的基本问题仍然存在。 通过性行为感染HIV-1值得注意的是，没有解释为什么在考虑了遗传变异后， 修改HIV-1进入和复制（最重要的是CCR 5 Δ-32），记录的HIV高暴露个体- 1表现出不同的结果，从快速感染到对HIV-1的长期自然抵抗 感染更好地了解这些表型可能会导致新的干预措施，以减少HIV-1 采集我们以前确定的功能性变体（错义/无义，非翻译区，或剪接位点） 在宿主基因中，这些基因与异性性获得性HIV-1感染的风险改变密切相关。值得注意地是， CD 101的遗传变异与HIV-1风险增加有最强的相关性，而AXL的变异与HIV-1风险增加有最强的相关性。 大大降低了风险。这两种基因都被认为调节宿主的炎症反应。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，循环T 与不具有功能性CD 101的供体相比，来自具有这些CD 101变体的供体的细胞和单核细胞 变异体，显示出更高的整体细胞活化，但某些HIV保护性干扰素的表达减少， 刺激基因相比之下，AXL是一种受体酪氨酸激酶，被认为通过骨髓细胞抑制 细胞免疫激活，可能通过抑制Toll样受体介导的先天免疫应答。 我们的总体假设是，宿主CD 101和AXL基因型的变异有助于改变 炎症稳态，从而影响HIV-1感染的风险。具体来说，我们假设， CD 101变异体通过增加HIV-1的丰度和活化而赋予HIV-1感染更高的风险 易感的T细胞，同时也损害了它们的先天抗病毒防御。相反，如果没有这些 AXL变体可能通过减少AXL变体所赋予的炎症而增强，从而降低HIV-1感染风险。 我们建议在三个目标中评估我们的假设：在目标1中，我们使用来自一个队列的基因组数据， 特征HIV-1获得表型在第二个HIV高风险非洲队列中复制， 平衡CD 101变异体对HIV-1易感性的影响。在目标2中，我们测试流行病学， 通过量化CD 101和AXL变异与 基因组数据已经存在的两个美国人群对HIV-1感染的易感性：一个包括 主要是与男性发生性关系的白色男性;第二个，种族多样的队列， 整个美国。在目标3中，我们将分子技术应用于血液和生殖器粘膜样本，这些样本存档在一个独特的 生物标本库，以直接将这些CD 101和AXL变异体的存在与宿主炎症 机制和离体HIV-1易感性。