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:
    10546199
  • 负责人:
  • 金额:
    $ 81.52万
  • 依托单位:
  • 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

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.
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。

项目成果

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Florian Hladik其他文献

Florian Hladik的其他文献

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{{ truncateString('Florian Hladik', 18)}}的其他基金

Impact of the menstrual cycle on granulysin-mediated immunity in the human cervicovaginal tract
月经周期对人宫颈阴道颗粒溶素介导的免疫的影响
  • 批准号:
    10616798
  • 财政年份:
    2022
  • 资助金额:
    $ 81.52万
  • 项目类别:
Impact of the menstrual cycle on granulysin-mediated immunity in the human cervicovaginal tract
月经周期对人宫颈阴道颗粒溶素介导的免疫的影响
  • 批准号:
    10450305
  • 财政年份:
    2022
  • 资助金额:
    $ 81.52万
  • 项目类别:
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:
    10664009
  • 财政年份:
    2022
  • 资助金额:
    $ 81.52万
  • 项目类别:
The regulatory role of natural progesterone in barrier immunity
天然黄体酮在屏障免疫中的调节作用
  • 批准号:
    10604809
  • 财政年份:
    2022
  • 资助金额:
    $ 81.52万
  • 项目类别:
The regulatory role of natural progesterone in barrier immunity
天然黄体酮在屏障免疫中的调节作用
  • 批准号:
    10708998
  • 财政年份:
    2022
  • 资助金额:
    $ 81.52万
  • 项目类别:
Vaginal immune effects of testosterone in transmasculine individuals
睾酮对跨男性个体的阴道免疫影响
  • 批准号:
    10369028
  • 财政年份:
    2021
  • 资助金额:
    $ 81.52万
  • 项目类别:
Cervicovaginal immune factors throughout the menstrual cycle: analysis of a cohort of Kenyan adolescents, systematic review, and meta-analysis
整个月经周期的宫颈阴道免疫因素:肯尼亚青少年队列分析、系统评价和荟萃分析
  • 批准号:
    10222496
  • 财政年份:
    2020
  • 资助金额:
    $ 81.52万
  • 项目类别:
Cervicovaginal immune factors throughout the menstrual cycle: analysis of a cohort of Kenyan adolescents, systematic review, and meta-analysis
整个月经周期的宫颈阴道免疫因素:肯尼亚青少年队列分析、系统评价和荟萃分析
  • 批准号:
    10046430
  • 财政年份:
    2020
  • 资助金额:
    $ 81.52万
  • 项目类别:
Extracellular vesicles in semen and genital HIV infection and immunity during heroin addiction and methadone or buprenorphine substitution therapy
海洛因成瘾和美沙酮或丁丙诺啡替代治疗期间精液中的细胞外囊泡和生殖器艾滋病毒感染和免疫
  • 批准号:
    9086328
  • 财政年份:
    2015
  • 资助金额:
    $ 81.52万
  • 项目类别:
Systems and carcinogenic impact assessment of topical microbicides on human mucosa
局部杀菌剂对人体粘膜的系统和致癌影响评估
  • 批准号:
    8922415
  • 财政年份:
    2015
  • 资助金额:
    $ 81.52万
  • 项目类别:

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