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
- 来源:
- 关键词:AccountingAfricaAfricanArchivesAutophagocytosisBiologicalBiological Specimen BanksBloodBlood CellsCD8-Positive T-LymphocytesCell NucleusCellsColitisCounselingCryopreservationDataDiabetes MellitusDiseaseEpidemiologyEquilibriumExhibitsExposure toGenesGeneticGenitalGenitaliaGenomeGenotypeHIVHIV riskHIV-1HeterosexualsHighly Active Antiretroviral TherapyHomeostasisImmuneImmunoglobulin DomainImmunologicsIn VitroIndividualInfectionInflammasomeInflammationInflammatoryInflammatory ResponseInnate Immune ResponseInterferonsInterleukin-2InterventionKnowledgeLeadLinkMediatingMedicineMolecularMucous MembraneMusMyeloid CellsNatural ResistanceNuclear TranslocationOutcomePathway interactionsPeripheral Blood Mononuclear CellPersonsPhenotypePopulationPredispositionPrevention approachProductionPublic HealthRNA SplicingReceptor Protein-Tyrosine KinasesRegulationRegulatory T-LymphocyteReportingResearch PersonnelResistanceRiskSamplingSingle Nucleotide PolymorphismSiteT-Cell ActivationT-LymphocyteTechniquesTestingTissuesToll-like receptorsUnited StatesUntranslated RegionsVariantWomanbasebase editingcell typechemokinecohortcytokinedensityethnic diversityfemale sex workergenetic variantgenital infectiongenome editinggenomic datahazardhigh riskhigh risk menimmune activationinfection riskmacrophagemen who have sex with menmonocytenovelnovel strategiesnuclear factors of activated T-cellspandemic diseasepathogenpre-exposure prophylaxispreventprogramsprotective allelerecruitrisk variantsample archivetraittranscription factortranscriptomevaginal 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.
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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
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$ 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
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Cervicovaginal immune factors throughout the menstrual cycle: analysis of a cohort of Kenyan adolescents, systematic review, and meta-analysis
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