Escape of maternal plasma broadly neutralizing antibody as a mechanism of mother to child HIV transmission
母体血浆广泛中和抗体的逃逸是艾滋病毒母婴传播的机制
基本信息
- 批准号:10327003
- 负责人:
- 金额:$ 74.42万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AccountingAntibodiesAntibody RepertoireAntiviral AgentsAutologousB cell repertoireBirthCase StudyCessation of lifeClinical ResearchClinical TrialsDevelopmentEpidemicEpitopesFutureGenerationsGoalsHIVHIV InfectionsHIV therapyHIV vaccineHIV-1ImmuneImmunoglobulin GImmunologicsImpairmentInfantInfectionInterventionLactationMapsMaternal antibodyMeasuresMediatingMonoclonal AntibodiesMother-to-child HIV transmissionMothersMutationPlasmaPopulationPregnancyPregnant WomenPremature InfantPrevention strategyProphylactic treatmentRegimenResistanceRiskRisk FactorsRoleRouteSafetySiteSpecificityTestingTimeVaccinationVaccinesVariantVertical Disease TransmissionViralVirusWomanantiretroviral therapybaseclinical developmentcohortdesigngenetic signaturehigh risk infantinfant infectionmaternal vaccinationneutralizing antibodynovelpediatric human immunodeficiency viruspediatric human immunodeficiency virus infectionplacental transferpredicting responsepressurepreventrepositoryresponserisk selectiontooltransmission processviral transmissionvirus envelope
项目摘要
Abstract
Over 150,000 HIV-1 infants are infected via mother to child transmission (MTCT) each year, accounting for
nearly 10% of the global annual HIV-1 infections. Even implementation of highly effective antiretroviral therapy
(ART) cannot prevent up to 5% of HIV-1 infected women from transmitting the virus to their infants. Thus,
approaches that synergize with ART will be needed to eliminate MTCT. The most promising interventions in
under clinical development to prevent HIV infection includes passive administration or active induction of
broadly-neutralizing antibodies (bnAbs). Yet, paradoxically, broad neutralization activity in maternal plasma
has been associated with risk of infant transmission, raising concerns about the safety of these approaches in
pregnancy. Thus, a better understanding of the role of maternal neutralizing activity and MTCT risk is needed
to develop effective bnAb-based interventions, which together with ART can more effectively block MTCT.
HIV MTCT is a unique transmission route that occurs in the setting of preexisting antibody raised against
autologous viruses. We previously found that transmitted/founder (T/F) viruses in infants were more resistant
to neutralization by paired maternal plasma than non-transmitted maternal viruses. Moreover, we established
that bnAb activity in maternal plasma can drive the development of circulating viral escape variants that
become infant T/F viruses. We hypothesize that multispecificity of maternal plasma bnAb activity is associated
with reduced risk of MTCT and autologous virus escape from these functional responses by infant T/F viruses
is a risk factor for transmission. Moreover, identifying bnAb escape variants that are fit for transmission is
important to designing combination bnAb approaches that can effectively prevent virus transmission. We will
use the following three Specific Aims to test our hypotheses: (1) Compare the specificity and polyfunctionality
of plasma bnAb activity from transmitting and non-transmitting mothers to assess the role of maternal bnAb
activity in vertical virus transmission risk. (2) Determine if infant T/F viruses and circulating viruses of
transmitting mothers are more resistant to plasma neutralizing activity compared to that of non-transmitted
maternal variants from transmitting and non-transmitting mothers. (3) Define genetic signatures responsible
for escape from the maternal Env-specific B cell repertoire among transmitted infant Env variants using a
panel of native Env trimer-specific mAbs isolated from transmitting mothers. Defining the specificity and
function of pre-existing maternal neutralizing antibodies that can reduce virus escape and impede
transmission will be critical to design novel passive and active vaccine approaches that can eliminate HIV
transmission from mothers to infants, and is a tool to define the population impact of the future use of bnAb-
based prophylaxis on HIV transmission dynamics.
摘要
每年有15万多名艾滋病毒1型婴儿通过母婴传播感染,
全球每年HIV-1感染的近10%。甚至实施高效抗逆转录病毒疗法
(ART)无法阻止高达5%的HIV-1感染妇女将病毒传播给婴儿。因此,在本发明中,
将需要与抗逆转录病毒疗法协同作用的方法来消除母婴传播。最有希望的干预措施,
在临床开发中预防HIV感染的方法包括被动给药或主动诱导
广泛中和抗体(bnAbs)。然而,矛盾的是,母体血浆中的广泛中和活性
与婴儿传播的风险有关,引起了人们对这些方法安全性的担忧,
怀孕因此,需要更好地了解母体中和活性和母婴传播风险的作用
制定有效的基于bnAb的干预措施,与抗逆转录病毒疗法一起可以更有效地阻止母婴传播。
艾滋病毒母婴传播是一种独特的传播途径,发生在预先存在的抗体,
自体病毒我们以前发现,婴儿中的传播/创始者(T/F)病毒更具耐药性,
与非传播的母体病毒相比,通过配对的母体血浆中和。此外,我们还建立了
母体血浆中的bnAb活性可以驱动循环病毒逃逸变体的发展,
变成婴儿T/F病毒。我们假设母体血浆bnAb活性的多特异性与
降低了婴儿T/F病毒引起的MTCT和自体病毒逃避这些功能反应的风险
是传播的危险因素。此外,鉴定适合于传播的bnAb逃逸变体是一个重要的步骤。
重要的是设计组合bnAb方法,可以有效地防止病毒传播。我们将
本研究主要从以下三个方面来验证我们的假设:(1)比较特异性和多功能性
来自传播和非传播母亲的血浆bnAb活性,以评估母体bnAb的作用
垂直病毒传播风险。(2)确定婴儿T/F病毒和
与非传播的母亲相比,传播母亲对血浆中和活性的抵抗力更强。
来自传播和非传播母亲的母体变异。(3)定义遗传特征
为了在传播的婴儿Env变体中逃避母体Env特异性B细胞库,使用
一组分离自传播母体的天然Env三聚体特异性mAb。定义特异性和
预先存在的母体中和抗体的功能可以减少病毒逃逸并阻止
传播将是至关重要的设计新的被动和主动疫苗的方法,可以消除艾滋病毒
从母亲到婴儿的传播,并且是确定未来使用bnAb的人群影响的工具-
基于艾滋病毒传播动态的预防。
项目成果
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Sallie R. Permar其他文献
Neonatal Cytomegalovirus Infection: Advocacy, Legislation, and Changing Practice
新生儿巨细胞病毒感染:倡导、立法和实践的改变
- DOI:
10.1016/j.clp.2024.10.008 - 发表时间:
2025-03-01 - 期刊:
- 影响因子:2.400
- 作者:
Ashley Stark;Chelsea M. Crooks;Sallie R. Permar;Kristin Elizabeth Dew Weimer - 通讯作者:
Kristin Elizabeth Dew Weimer
Maternal immune protection against infectious diseases
针对传染病的母体免疫保护
- DOI:
10.1016/j.chom.2022.04.007 - 发表时间:
2022-05-11 - 期刊:
- 影响因子:18.700
- 作者:
Stephanie N. Langel;Maria Blasi;Sallie R. Permar - 通讯作者:
Sallie R. Permar
Breast milk delivery of an engineered dimeric IgA protects neonates against rotavirus
工程化二聚体免疫球蛋白 A 的母乳递送可保护新生儿免受轮状病毒感染
- DOI:
10.1016/j.mucimm.2025.01.002 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:7.600
- 作者:
Stephanie N. Langel;Claire E. Otero;Justin T. Steppe;Caitlin A. Williams;Tatiana Travieso;Jerry Chang;Helen Webster;Lauren E. Williamson;James E. Crowe;Harry B. Greenberg;Huali Wu;Christoph P. Hornik;Katayoun Mansouri;Robert J. Edwards;Victoria Stalls;Priyamvada Acharya;Maria Blasi;Sallie R. Permar - 通讯作者:
Sallie R. Permar
Advances in nanomaterial vaccine strategies to address infectious diseases impacting global health
用于解决影响全球健康的传染病的纳米材料疫苗策略的进展
- DOI:
10.1038/s41565-020-0739-9 - 发表时间:
2020-08-17 - 期刊:
- 影响因子:34.900
- 作者:
Chelsea N. Fries;Elizabeth J. Curvino;Jui-Lin Chen;Sallie R. Permar;Genevieve G. Fouda;Joel H. Collier - 通讯作者:
Joel H. Collier
Sallie R. Permar的其他文献
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{{ truncateString('Sallie R. Permar', 18)}}的其他基金
Identifying and modeling immune correlates of protection against congenital CMV transmission after primary maternal infection
原发性母体感染后预防先天性巨细胞病毒传播的免疫相关性的识别和建模
- 批准号:
10677439 - 财政年份:2023
- 资助金额:
$ 74.42万 - 项目类别:
Immunogenicity and Efficacy of SARS-CoV-2 stabilized prefusion Spike protein vaccines in infant rhesus macaques
SARS-CoV-2 稳定预灌注 Spike 蛋白疫苗在幼年恒河猴中的免疫原性和功效
- 批准号:
10223633 - 财政年份:2020
- 资助金额:
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