Elucidating the mechanism of progesterone-induced permissivity in the upper female reproductive tract
Elucidating the mechanism of progesterone-induced permissivity in the upper female reproductive tract
批准号:
9270196
负责人:
Nadia R Roan
金额:
$39.63万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-26 至 2021-08-31
关键词:
AIDS preventionAccountingAffectAgeAntiviral AgentsApicalAutologousBiological AssayBiological ModelsBiopsyBypassCD4 Positive T LymphocytesCellsCervicalCoculture TechniquesColumnar EpitheliumComplexConditioned Culture MediaContraceptive AgentsCytometryDataEndometrialEndometriumEpidemicEpithelialEpithelial CellsEpitheliumEstrogensEventExhibitsFemaleFibroblastsGenital systemGoalsGonadal Steroid HormonesHIVHIV InfectionsHIV riskHumanImmuneInfectionInflammatoryIntestinal MucosaLeadLinkLuteal PhaseMediatingMedroxyprogesterone 17-AcetateModelingMolecularPatientsPermeabilityPhenotypePopulationPredispositionPreventionProgesteroneProgestinsProteinsRiskSIVSLPI geneSeminal fluidSexual TransmissionSideSiteSynthetic ProgestogensSystemT-LymphocyteTestingThird Pregnancy TrimesterTissuesVaginaViralVirus ReplicationWomanbasecell typecytokinedesignepidemiologic datainhibitor/antagonistinsightmalemicrobicidemonolayernonhuman primatenovel strategiespathogenpenis foreskinpreventreconstitutionreproductivereproductive tractresponsesensorsexual HIV transmissiontooltranscriptome sequencingtransmission processvaginal microbicide
中文摘要
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英文摘要
PROJECT SUMMARY / ABSTRACT:
Worldwide, women bear the brunt of the HIV epidemic, and an effective means to prevent HIV transmission to
women remains an elusive goal. Achieving this goal is hampered by our incomplete understanding of the early
events in the female reproductive tract (FRT) during sexual transmission. In particular, how resident HIV-
susceptible and non-susceptible cells affect viral replication, and sense and respond to HIV infection, are not
well understood. Although the upper FRT harbors HIV-susceptible cells, is exposed to semen components,
and is infected early in SIV transmission models, it is understudied as a portal of entry for HIV. In cycling
women, the endometrium of the upper FRT is extensively remodeled in response to the sex steroids estrogen
and progesterone. Progesterone and progestins, synthetic mimics of progesterone, are associated with
increased susceptibility to HIV infection in humans and in non-human primate models. Therefore,
understanding how these compounds affect the endometrium may yield insights into how HIV establishes
infection through this tissue. In our preliminary studies, progesterone decreased barrier function of endometrial
epithelial cells, which can facilitate entry of HIV from the luminal cavity into the stromal compartment of the
endometrium. Within the stroma resides a dense population of endometrial stromal fibroblasts. Although these
cells were not permissive to HIV infection, in co-culture with CD4+ T cells they increased infection by up to 81-
fold. In contrast, when progesterone was absent, epithelial barrier integrity was maintained, and the intact layer
of endometrial epithelial cells restricted infection by eliciting an antiviral state in co-cultured CD4+ T cells. Using
an ex vivo system reconstituted from cells from endometrial biopsies, we will examine the molecular
mechanisms responsible for progesterone-induced leakiness (Specific Aim 1), the increased susceptibility to
infection mediated by stromal fibroblasts (Specific Aim 2), and epithelia-induced viral restriction (Specific Aim
3) in the upper FRT. Because progesterone-induced epithelial permeability may also occur in the lower FRT,
we will additionally test this model using cells isolated from ectocervical biopsies. The proposed studies will
deepen our understanding of HIV transmission and restriction in the FRT and provide a robust ex vivo model
system to examine the complex interplay between sex steroids and tissue-resident cells in the context of HIV
susceptibility. This system and the phenotyping tools we have established can also be adapted to study HIV
transmission and restriction in other mucosal portals of entry such the intestinal mucosa and the male foreskin.
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Exploring the Role of Semen Amyloids in Promoting HIV Infection and Fertilization
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依托单位:
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依托单位:
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财政年份:--
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依托单位:
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批准号:9323802
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项目类别:
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资助金额:$43.02万
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财政年份:--
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负责人:Nadia R Roan
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依托单位:
海外基金