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.
为了在美国和世界范围内结束这一流行病,必须采取多种方法,
实施包括早期发现、预防战略、更高的治疗功效和可及性的措施,
希望能找到疫苗和治愈方法HIV感染细胞的潜在储存库的存在
是找到艾滋病治愈方法的主要障碍。潜伏性感染与无法检测到的
病毒基因表达水平,似乎是非细胞病变。几种治疗性干预措施,
潜伏艾滋病毒正在调查中。其中,“休克和杀死”策略已进入人体临床试验
艾滋病毒携带者(PLWH)。制定这些和其他干预措施以遏制这一流行病,
不同的人群,以及这些策略的疗效是否可能在特定的生物学功能方面有所不同,
因素性激素,包括雌激素、睾酮和孕酮,是性行为的关键介质。
发展除了在性发育中的主要作用外,性激素受体还存在于免疫系统中。
细胞,可以影响HIV感染,HIV转录以及免疫细胞功能。但我们
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,
制定治疗干预措施,旨在治愈艾滋病毒携带者,包括妇女,
变性人妇女占全世界所有感染者的一半以上,变性人占
在美国,高达0.6%的育龄成年人感染艾滋病毒的风险约高出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
在变性过程中使用的激素替代疗法可能会干扰治愈
战略是完全未知的。
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作为HIV潜伏期的一部分。
以及用于变性人激素替代疗法的抗雄激素可能会影响
建立HIV潜伏期。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(LRA)的活性,包括用于HIV根除临床试验的LRA。
在目标2中,我们打算评估目前临床上使用的Toll样受体(TLR)激动剂的活性是否与Toll样受体(TLR)激动剂的活性相关。
根除艾滋病毒的试验可能受到性激素和抗雄激素的影响。最后,在目标3中,
探讨性激素和抗雄激素是否影响NK细胞活性。NK细胞是先天免疫系统的一部分,
并在控制艾滋病毒感染方面发挥重要作用。性激素已经被证明
对NK细胞抗肿瘤活性有不良影响。然而,关于性激素是否会影响
抗艾滋病毒活性。在设计目标策略时,我们的研究将特别有趣
努力消除包括妇女和变性人在内的不同艾滋病毒携带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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