Hormonal control of HIV latency
HIV潜伏期的激素控制
基本信息
- 批准号:10650164
- 负责人:
- 金额:$ 39.88万
- 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:2020-06-24 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAgeAgonistAndrogen AntagonistsBasic ScienceBiologicalBiological FactorsBiologyCD4 Positive T LymphocytesCell modelCell physiologyCellsClinicalClinical TrialsDevelopmentDiseaseDisease ProgressionDoseEarly DiagnosisEffector CellEpidemicEstradiolEstrogensFemaleFunding OpportunitiesFutureGenderGene ExpressionGenerationsGenetic TranscriptionGonadal Steroid HormonesHIVHIV AntibodiesHIV InfectionsHealthHormonalHormone ReceptorHormone replacement therapyImmuneImmune systemIndividualInfectionInnate Immune SystemInterventionInvestigationKiller CellsKnowledgeLifeMaintenanceMalignant NeoplasmsMediatingMediatorMenopauseMenstruationMucosal Immune ResponsesNatureParticipantPatientsPersonsPlayPopulationPregnancyPrevention strategyProgesteronePropertyReplacement TherapyResearchResearch PersonnelRoleSexual DevelopmentSexual ReassignmentShockSpironolactoneTestingTestosteroneTherapeuticTherapeutic InterventionTimeToll-like receptorsTranscriptional ActivationTreatment EfficacyVaccinesViralViral GenesWomanantiretroviral therapycis-femalecis-maleclinically relevantdesignexperiencefallshigh riskhormone regulationimmune activationinterestlatent HIV reservoirlatent infectionmaleoutreachreactivation from latencyreproductiveresearch clinical testingsextherapeutic developmenttransgendertumor
项目摘要
In order to end the epidemic in the US and worldwide a combination of approaches must be
implemented that include early detection, prevention strategies, higher treatment efficacy and accessibility,
outreach, and hopefully a vaccine and a cure. The existence of a latent reservoir of HIV-infected cells
constitutes the major impediment towards finding an HIV cure. Latent infection is associated with undetectable
levels of viral gene expression and appears to be non-cytopathic. Several therapeutic interventions against
latent HIV are under investigation. Among them, ‘shock and kill’ strategies have reached clinical trials in people
living with HIV (PLWH). The development of these and other interventions to curb the epidemic has to consider
different populations and whether the efficacy of these strategies may vary in function of specific biological
factors. Sex hormones, including estrogen, testosterone and progesterone, are critical mediators of sexual
development. Besides their main role in sexual development, sex hormone receptors are present in immune
cells and can influence HIV infection, HIV transcription as well as immune cell function. However, we are
limited in our understanding whether and how sex hormones could influence cure strategies. This is crucial in
the development of therapeutic interventions aimed towards an HIV cure in PLWH, including women and
transgender. Women represent more than half of all the infections worldwide and transgender, which account
for up to 0.6% of reproductive age adults in the US, are at approximately 49-fold higher risk of acquiring HIV
infection. These populations will tremendously benefit from cure approaches. However, whether sex hormones
and hormonal replacement therapies used during gender reassignment could potentially interfere with cure
strategies is completely unknown.
In Aim 1, we proposed to use a primary cell model of HIV latency to address whether sex hormones as
well as antiandrogens used in hormonal replacement therapy for transgender individuals could influence the
establishment of HIV latency. We will also evaluate whether sex hormones and antiandrogens influence the
activity of a panel of latency-reversing agents (LRAs), including LRAs used in clinical trials for HIV eradication.
In Aim 2, we intend to evaluate whether the activity of toll-like receptors (TLRs) agonists currently under clinical
trials to eradicate HIV could be influenced by sex hormones and antiandrogens. Finally, in Aim 3 we will
explore whether sex hormones and antiandrogens influence NK cell activity. NK cells are part of the innate
immune system and play an important role in controlling HIV infection. Sex hormones have been shown to
detrimentally affect NK anti-tumoral activity. However, less is known on whether sex hormones could influence
their anti-HIV activity. Our studies will be of particular interests at the time of designing strategies aimed
towards eliminating the HIV latent reservoir in different PLWH, including women and transgender, and will
inform of the role that sex hormones could play in current and future HIV cure approaches.
为了结束美国和世界范围内的流行病,必须采取多种方法
实施包括早期发现、预防策略、更高的治疗功效和可及性,
外展活动,希望有疫苗和治疗方法。 HIV感染细胞的潜在储存库的存在
是寻找艾滋病毒治疗方法的主要障碍。潜伏感染与无法检测到的相关
病毒基因表达水平,并且似乎是非细胞病变的。几种治疗干预措施
潜伏的艾滋病毒正在接受调查。其中,“电击杀戮”策略已进入人体临床试验
艾滋病毒感染者(PLWH)。制定这些和其他遏制流行病的干预措施必须考虑
不同人群以及这些策略的功效是否可能因特定生物功能而异
因素。性激素,包括雌激素、睾酮和黄体酮,是性功能的重要调节因子
发展。除了在性发育中发挥主要作用外,性激素受体还存在于免疫系统中。
细胞并可以影响 HIV 感染、HIV 转录以及免疫细胞功能。然而,我们是
我们对性激素是否以及如何影响治疗策略的理解有限。这一点至关重要
制定旨在治愈艾滋病毒感染者(包括妇女和儿童)的治疗干预措施
跨性别。女性占全球所有感染者和跨性别者的一半以上,其中
美国高达 0.6% 的育龄成年人感染 HIV 的风险大约高出 49 倍
感染。这些人群将从治疗方法中受益匪浅。然而,性激素是否
性别重置过程中使用的激素替代疗法可能会干扰治愈
策略完全未知。
在目标 1 中,我们建议使用 HIV 潜伏期的原代细胞模型来解决性激素是否与
以及跨性别者激素替代疗法中使用的抗雄激素可能会影响
HIV潜伏期的建立。我们还将评估性激素和抗雄激素是否影响
一组潜伏期逆转剂 (LRAs) 的活性,包括用于根除 HIV 临床试验的 LRA。
在目标 2 中,我们打算评估目前临床上是否存在 Toll 样受体 (TLR) 激动剂的活性。
根除艾滋病毒的试验可能会受到性激素和抗雄激素的影响。最后,在目标 3 中,我们将
探讨性激素和抗雄激素是否影响 NK 细胞活性。 NK细胞是先天性细胞的一部分
免疫系统在控制艾滋病毒感染方面发挥着重要作用。性激素已被证明可以
不利地影响 NK 抗肿瘤活性。然而,对于性激素是否会影响性激素,人们知之甚少。
他们的抗艾滋病毒活性。在设计旨在实现目标的策略时,我们的研究将特别令人感兴趣
消除不同感染者(包括妇女和跨性别者)中的艾滋病毒潜伏库,并将
告知性激素在当前和未来的艾滋病毒治疗方法中可能发挥的作用。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
IL-15 and N-803 for HIV Cure Approaches.
- DOI:10.3390/v15091912
- 发表时间:2023-09-12
- 期刊:
- 影响因子:0
- 作者:Howard JN;Bosque A
- 通讯作者:Bosque A
An ultrasensitive planar array p24 Gag ELISA to detect HIV-1 in diverse biological matrixes.
- DOI:10.1038/s41598-021-03072-7
- 发表时间:2021-12-08
- 期刊:
- 影响因子:4.6
- 作者:Levinger C;Howard JN;Cheng J;Tang P;Joshi A;Catalfamo M;Bosque A
- 通讯作者:Bosque A
HIV Pathogenesis in the Human Female Reproductive Tract.
- DOI:10.1007/s11904-021-00546-1
- 发表时间:2021-04
- 期刊:
- 影响因子:4.6
- 作者:Rodriguez-Garcia, Marta;Connors, Kaleigh;Ghosh, Mimi
- 通讯作者:Ghosh, Mimi
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Alberto Bosque其他文献
Alberto Bosque的其他文献
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{{ truncateString('Alberto Bosque', 18)}}的其他基金
Defining HIV Env protein expression in latently infected cells
定义潜伏感染细胞中的 HIV 包膜蛋白表达
- 批准号:
10762524 - 财政年份:2023
- 资助金额:
$ 39.88万 - 项目类别:
Ultrasensitive Env Detection Assay for Broadly Neutralizing Antibody Screening
用于广泛中和抗体筛选的超灵敏包膜检测分析
- 批准号:
10676393 - 财政年份:2023
- 资助金额:
$ 39.88万 - 项目类别:
Pathways modulating memory-like properties in NK cells and their impact on HIV control
调节 NK 细胞记忆样特性的途径及其对 HIV 控制的影响
- 批准号:
10534402 - 财政年份:2022
- 资助金额:
$ 39.88万 - 项目类别:
Pathways modulating memory-like properties in NK cells and their impact on HIV control
调节 NK 细胞记忆样特性的途径及其对 HIV 控制的影响
- 批准号:
10673150 - 财政年份:2022
- 资助金额:
$ 39.88万 - 项目类别:
Training in HIV Persistence, Co-morbidities and Therapeutics
HIV 持续性、合并症和治疗方面的培训
- 批准号:
10326881 - 财政年份:2021
- 资助金额:
$ 39.88万 - 项目类别:
Training in HIV Persistence, Co-morbidities and Therapeutics
HIV 持续性、合并症和治疗方面的培训
- 批准号:
10657673 - 财政年份:2021
- 资助金额:
$ 39.88万 - 项目类别:
Developing Pathogen Recognition Receptor Agonists as Latency Reversing Agents
开发病原体识别受体激动剂作为潜伏期逆转剂
- 批准号:
9501675 - 财政年份:2016
- 资助金额:
$ 39.88万 - 项目类别:
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