Genetic Risk of HIV Acquisition: Mechanisms of Resilience
感染艾滋病毒的遗传风险:恢复机制
基本信息
- 批准号:10077116
- 负责人:
- 金额:$ 25.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdoptionAffectAfricanAnti-Retroviral AgentsApplications GrantsBehavioralBindingBiologicalBiological FactorsCCR5 geneCD4 Positive T LymphocytesCellsCodeColorCommunitiesComplexComprehensionCountryDataDeveloped CountriesDiseaseDistalDrug usageEnvironmental ExposureEpidemicEpidemiologyExposure toGaysGene FrequencyGenesGeneticGenetic PolymorphismGenetic RiskGenetic TranscriptionGenetic studyGleanGrantHIVHIV InfectionsHIV-1HaitiHematologic AgentsHeritabilityHomozygoteImmune systemImmunologicsIn VitroIndividualInfectionInterventionLeadLesbian Gay Bisexual Transgender QueerLos AngelesMammalian CellMediatingMethodsModernizationMothersMutationNew YorkPharmaceutical PreparationsPharmacotherapyPhenotypePlayPopulationPopulation GeneticsPredispositionPreventionPrevention strategyProteinsResistance to infectionRiskRisk FactorsRoleRouteSepsisSexually Transmitted DiseasesSurfaceTestingUnsafe SexValidationVertical Disease TransmissionViralVirusWorkbaseblood productcase controlcausal variantcell typecohortcondomscytokinedrug abstinencegenetic analysisgenetic associationgenetic variantgenome wide association studygenome-widehigh riskhigh risk behaviorhigh risk populationimprovedinfection riskinflammatory markerintravenous administrationintravenous drug usemennovelpolygenic risk scorepre-exposure prophylaxisprematurepreventreceptorresiliencerisk variantsexsocial stigmastatisticstrait
项目摘要
PROJECT SUMMARY/ABSTRACT
This new R21 submission is entitled “Genetic Risk of HIV Acquisition: Mechanisms of Resilience”. Soon after
the identification of a new disease amongst gay men in Los Angeles and New York, originally called GRID,
epidemiological evidence suggested a sexually transmitted infection, which was then confirmed in populations
in Haiti and African identified with infection with HIV-1. In addition to infection through sex, intravenous
administration of contaminated blood products or drug use could lead to infection, as well as mother to child
transmission. Blood infection was identified as the highest risk, with different routes of sexual exposure
associated with different identifiable risks of infection. Before antiretroviral drug therapy became available,
around one third of babies born to infected mothers were infected, while two thirds were not. Thus, it appeared
that epidemiological and behavioral factors could predict HIV-1 susceptibility. However, individuals exposed to
HIV infection who had not became infected helped identify the defective Δ32 form of CCR5 receptor which
misfolded at the surface of a CD4+ cell and could not be infected, and in homozygote form, led to resistance to
infection with R5 using viruses. However, no genome-wide significant polymorphisms were found associated
with HIV-1 acquisition, which has led the field to move away from genetic association analyses. We were puzzled
from recent studies of sex workers exposed to HIV-1 who did not become infected despite high risk behavior
and wondered if genetic resilience to HIV-1 acquisition had been missed. Population genetic methods have
developed substantially in recent years, now allowing for powerful, biologically-informative analyses even in
moderately-sized gene wide association studies (GWAS). In preliminary data, we reanalyzed the largest GWAS
of HIV-1 acquisition and used gene-level enrichment analyses and polygenic risk scoring to identify novel genes
and inflammatory markers associated with acquisition risk. We have shown that HIV-1 acquisition is a surprisingly
heritable trait, and that certain cytokines are associated with HIV-1 resilience. These findings could lead to
potential new ways of preventing HIV-1 infection, including targeted interventions to those at highest risk. In this
grant, we will extend our analyses of the genetics of acquisition to validation cohorts including non-European
ancestry and determine mechanisms of immunological resilience. A better understanding of biological factors
influencing acquisition has the potential to develop our basic comprehension of HIV-1 acquisition, improve
prevention strategies and reduce social stigma.
项目摘要/摘要
这种新的R21提交名为“艾滋病毒获取的遗传风险:弹性的机制”
在洛杉矶和纽约的男同性恋者中鉴定出一种新疾病,最初称为Grid,
流行病学证明了一种性传播感染,这在人群中得到了证实
在海地和非洲人,除了感染外,还静脉
受污染的血液产品或吸毒的施用可能导致感染,以及母亲对儿童
传播。
与不同可识别的感染风险相关。
被感染的母亲出生的婴儿中有三分之一被感染,而三分之一没有
这种流行病学和行为可能可以预测HIV-1的易感性。
HIV HO没有被感染帮助帮助有助于有助于Δ32形式的CCR5受体,该形式的受体有帮助
在CD4+细胞的表面错误折叠,无法感染,并以纯合形式导致了对
但是,使用病毒感染R5。
随着HIV-1采集,该领域从遗传关联分析中移开了困惑
从最近对暴露于HIV-1的性工作者的研究中,尽管行为高风险行为
并想知道遗传对HIV-1的恢复能力是否遗漏了人口遗传学方法。
最近一年开发了基本的发展,现在允许进行强大的,具有生物信息的分析
中等大小的基因研究(GWAS)。
HIV-1获取和美元基因级富集和多基因风险评分的新基因
与采集风险相关的炎症标记。
可遗传的特征,这些发现与HIV-1的弹性有关。
预防HIV-1感染的潜在方法,包括对风险最高的针对性干预措施
Grant,我们将将获取遗传学的分析扩展到包括非欧洲的验证群体
祖先并确定免疫学弹性的机制。
影响获取的潜力有可能开发我们的HIV-1获取基本汇编,改进
预防策略并减少社会污名。
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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DOUGLAS F NIXON其他文献
DOUGLAS F NIXON的其他文献
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