Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)
阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响
基本信息
- 批准号:10372984
- 负责人:
- 金额:$ 53.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-12 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:15 year old16S ribosomal RNA sequencingAIDS preventionActive Biological TransportAddressAdenineAdherenceAdolescentAdolescent and Young AdultAdultAffectAgeAnti-Retroviral AgentsBacteriaBacterial VaginosisBehavioralBindingBiologic CharacteristicBiological AssayBiological AvailabilityBiological FactorsBiopsyBlack raceCell SeparationCellsCenters for Disease Control and Prevention (U.S.)CervicalClinicalClinical ResearchClinical TrialsComplexContraceptive UsageDapivirineDataDevelopmentDiffuseDoseDrug FormulationsDrug KineticsDrug TransportEffectivenessEndocytosisEpidemicEquilibriumEthnic OriginFemaleFlow CytometryFormulationFrequenciesGardnerellaGelGene ExpressionHIVHIV riskHeterosexualsHumanImmunoglobulin AImmunoglobulin GImmunoglobulinsIn VitroIncubatedIndividualInfectionInflammationInflammatoryIntegraseIntegrase InhibitorsInterventionKnowledgeLactobacillusLatinoLinkLiquid substanceMeasuresMetabolicMetagenomicsMetronidazoleMucositisMucous MembraneOrganic Anion TransportersOutcomeParticipantPathway interactionsPharmaceutical PreparationsPharmacologyPhasePilot ProjectsPopulationPredispositionPreventionProdrugsPropertyPublic HealthRaceRiskSamplingSeminal fluidSwabT-LymphocyteTechniquesTechnologyTenofovirTestingTimeTissuesTopical applicationTranslatingUnited StatesVaginaVulnerable PopulationsWomanage groupbacterial communitybasecervicovaginalcohortdesigndrug metabolismdysbiosisepidemiology studyfecal microbiomehigh riskmenmetabolomemetatranscriptomicsmicrobial communitymicrobiomemicrobiotanext generationnoveloral carephase 1 studyphase III trialpre-exposure prophylaxispreclinical developmentreproductive tractresponsestandard of careuptakevaginal microbiomevaginal microbiotayoung woman
项目摘要
Globally, young women represent one of the most vulnerable groups at risk for HIV acquisition highlighting the
need for safe, acceptable and effective prevention products. Outcomes in pre-exposure prophylaxis (PrEP)
clinical trials have been uniformly disappointing in this high-risk age group, reflecting both behavioral and
biological characteristics. The efficacy of PrEP reflects a balance between host susceptibility to HIV and the
concentration of drug present in host target cells at the time of exposure. One of the most important biological
factors that modulates both the risk of HIV acquisition and the pharmacokinetics and efficacy of topically
delivered PrEP products is the vaginal microbiome. Recent studies highlight the complex mechanisms by which
individual bacteria and their metabolic products adversely affect the pharmacokinetics of several different PrEP
drugs by competing with human cells for drug uptake, inhibiting drug transport into human cells, or metabolizing
drugs. Moreover, bacterial vaginosis, which is common in adolescent and young women, is associated with
increased HIV risk, possibly reflecting mucosal inflammation. However, the precise mechanisms linking dysbiosis
with inflammation and the cumulative effect of the microbiome on PrEP pharmacokinetics are not defined. This
application will address this critical knowledge gap and test the overarching hypothesis that vaginal dysbiosis in
adolescent and young adult women reduces PrEP efficacy by promoting mucosal inflammation, increasing HIV
risk, and decreasing local drug bioavailability. We will use cutting edge technologies including flow cytometry
based bacterial cell sorting of immunoglobulin-coated bacteria combined with 16S rRNA sequencing (IgSeq),
metagenomic and metatranscriptomic sequencing to evaluate the link between vaginal dysbiosis and mucosal
inflammation. Vaginal swabs will be collected from adolescent and young women with symptomatic bacterial
vaginosis (BV) before and after standard of care treatment and from asymptomatic controls (no BV) who are
frequency matched for age, race/ethnicity and contraceptive use. We will characterize the total bacterial
population and the IgA and/or IgG coated and uncoated bacteria and correlate findings with measures of genital
tract inflammation including gene expression in vaginal biopsy tissue. We predict that the composition of Ig
coated bacteria will differ before and after BV treatment and compared to controls and will identify bacteria that
drive genital tract inflammation. Using the clinical samples, we will determine the cumulative effects of bacterial
communities and their metabolome on tenofovir-based PrEP (including tenofovir and its prodrugs), assess which
mechanisms dominate, and explore potential interventions that might promote more consistent drug
pharmacology. We will also evaluate “next-generation” PrEP products including integrase inhibitors. Together,
these results will provide rationale for the selection, dosing and formulation of drugs alone or in combination for
optimal prevention of HIV in young women.
在全球范围内,年轻女性是面临感染艾滋病毒风险的最脆弱群体之一
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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Betsy C. Herold其他文献
Amp C β-lactamase-producing Escherichia coli in neonatal meningitis: diagnostic and therapeutic challenge
新生儿脑膜炎中产 Amp C β-内酰胺酶的大肠杆菌:诊断和治疗挑战
- DOI:
- 发表时间:
2006 - 期刊:
- 影响因子:2.9
- 作者:
E. Fakioglu;A. Queenan;Karen Bush;Stephen G. Jenkins;Betsy C. Herold - 通讯作者:
Betsy C. Herold
1192: Placental transfer of HSV-specific antibodies from mothers to newborns
- DOI:
10.1016/j.ajog.2019.11.1204 - 发表时间:
2020-01-01 - 期刊:
- 影响因子:
- 作者:
Aakash Mahant;Fatima A. Estrada Trejo;Anayeli Correa;Lip Loh;Benjamin Galen;Betsy C. Herold - 通讯作者:
Betsy C. Herold
GLYCOPROTEIN C(gC) of HERPES SIMPLEX VIRUS (HSV) TYPE 1 BINDS TWO DISTINCT POLYSACCHARIDE POPULATIONS WITHIN HEPARIN. † 704
- DOI:
10.1203/00006450-199704001-00724 - 发表时间:
1997-04-01 - 期刊:
- 影响因子:3.100
- 作者:
Susan I. Gerber;Ronald E. Hileman;Jonathan R. Fromm;Robert J. Linhardt;Betsy C. Herold - 通讯作者:
Betsy C. Herold
50 Years Ago in <span class="small-caps"><em>The Journal of Pediatrics</em></span>: Revisiting a Diagnostic Dilemma 50 Years Later: Partially Treated Bacterial Meningitis
- DOI:
10.1016/j.jpeds.2020.04.013 - 发表时间:
2020-10-01 - 期刊:
- 影响因子:
- 作者:
Brenda I. Anosike;Betsy C. Herold - 通讯作者:
Betsy C. Herold
Mounting Evidence Suggests Safety and Efficacy of Immunizations Posttransplantation
越来越多的证据表明移植后免疫接种的安全性和有效性
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:8.8
- 作者:
R. Madan;Betsy C. Herold - 通讯作者:
Betsy C. Herold
Betsy C. Herold的其他文献
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{{ truncateString('Betsy C. Herold', 18)}}的其他基金
Optimizing the Generation of Monoclonal Antibodies for Prevention and Treatment of HSV Disease
优化用于预防和治疗 HSV 疾病的单克隆抗体的生成
- 批准号:
10717320 - 财政年份:2023
- 资助金额:
$ 53.34万 - 项目类别:
Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)
阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响
- 批准号:
10612363 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
Impact of the vaginal microbiome on topical HIV pre-exposure prophylaxis (PrEP)
阴道微生物组对局部 HIV 暴露前预防 (PrEP) 的影响
- 批准号:
9914110 - 财政年份:2019
- 资助金额:
$ 53.34万 - 项目类别:
Mechanisms Underlying the HIV-HSV-2 Syndemic
HIV-HSV-2 综合征的潜在机制
- 批准号:
10063474 - 财政年份:2017
- 资助金额:
$ 53.34万 - 项目类别:
Mechanisms Underlying the HIV-HSV-2 Syndemic
HIV-HSV-2 综合征的潜在机制
- 批准号:
10305681 - 财政年份:2017
- 资助金额:
$ 53.34万 - 项目类别:
Impact of Mucosal Immune Enviroment and semen on Prep and PD
粘膜免疫环境和精液对 Prep 和 PD 的影响
- 批准号:
8448474 - 财政年份:2013
- 资助金额:
$ 53.34万 - 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring PrEP
药物在正确的地方
- 批准号:
9132494 - 财政年份:2013
- 资助金额:
$ 53.34万 - 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring Pr*
药物在正确的地方
- 批准号:
8435762 - 财政年份:2013
- 资助金额:
$ 53.34万 - 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring PrEP
药物在正确的地方
- 批准号:
8988532 - 财政年份:2013
- 资助金额:
$ 53.34万 - 项目类别:
Drug at the Right Place & Concentration: Optimizing Combination Vaginal Ring Pr*
药物在正确的地方
- 批准号:
8606159 - 财政年份:2013
- 资助金额:
$ 53.34万 - 项目类别:














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