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

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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