Retooling Natural killers cells (NK) and mucosal Innate lymphoid cells (ILCs) for an effective HIV vaccine
重组自然杀伤细胞 (NK) 和粘膜先天淋巴细胞 (ILC) 以获得有效的 HIV 疫苗
基本信息
- 批准号:9270328
- 负责人:
- 金额:$ 15.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-04 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:ALVACATAC-seqAchievementAcquired Immunodeficiency SyndromeAdjuvantAgonistAryl Hydrocarbon ReceptorBrassicaceaeBroccoli - dietaryC57BL/6 MouseCarbazolesCellsContainmentDataDevelopmentEpigenetic ProcessFamilyFoodGoalsHIVHIV Envelope Protein gp120HIV InfectionsHIV vaccineHomeostasisHumanImmunityIndole-3-CarbinolInfectionInfection preventionInnate Immune ResponseInterleukin-17KnowledgeLeadLigandsLymphoid CellMacaca mulattaMediatingMemoryMorbidity - disease rateMucosal ImmunityMucous MembraneMultivariate AnalysisMusNatural ImmunityNatural Killer CellsOralPeripheralPhasePreventive vaccineProteinsRegulatory ElementRiskRoleSIVSIV VaccinesTestingVaccinationVaccinesVegetablesVirusadaptive immune responseadaptive immunityaluminum sulfateantiretroviral therapyaryl hydrocarbon receptor ligandcombinatorialdesignexperimental studyimprovedin vivomucosal sitenatural killer cell protein 44-kDanovelnovel strategiespreventrectalresponsesimian immunodeficiency virus gp120transcription factortransmission processvaccination strategyvaccine candidatevaccine efficacyvaccine trialvectorvector vaccine
项目摘要
Project Summary
Despite remarkable achievements in the treatment, the rates of new HIV infections
continue to grow, and AIDS remains the fifth largest morbidity in the world. Consequently, the
development of an effective vaccine or combinatorial approaches that prevent HIV transmission is
urgently needed. The RV144 vaccine trial, which used ALVAC-HIV vector and alum-adjuvanted
AIDSVAX B/E gp120 protein, is the first, and so far the only, HIV vaccine to demonstrate limited but
significant protection against HIV acquisition. While most HIV vaccines have been designed to elicit
adaptive immunity, vaccine-mediated innate immune responses have been overlooked. HIV
infection occurs mainly at the mucosal site, where localized foci are formed before the systemic
spread of the virus. Thus, enhancing mucosal immunity would be an effective way to prevent
infection. Increasing evidence shows the potential role of natural killer cells (NK) and innate
lymphoid cells group-3 (ILC3) in HIV containment, and their ability to modulate adaptive immune
responses and mucosal homeostasis. Mounting protective NK cell responses and enhancing
mucosal immunity by augmenting the functions of ILC3 would be an effective way of preventing
infection. However, little is known about HIV vaccine-induced peripheral NK cells and mucosal
ILC3 responses. To our knowledge, no vaccine study has focused on modulating NK or ILC3 to
improve protection from HIV infection. We have recapitulated the similar protection observed in the
RV144 trial in rhesus macaques using the same vaccination strategy. My preliminary data
demonstrate the induction of early and durable NK and ILC3 responses in peripheral and mucosal
sites following vaccination and a correlation between IL-17 producing NKp44+ILCs in the gut with
reduced risk of infection in the multivariate analysis. Thus, I hypothesize that the ALVAC-SIV
gp120/alum vaccination, combined with augmented NK and ILC3 responses, would enhance
vaccine efficacy against HIV/SIV infection. To test this hypothesis, I will investigate the effect of
ALVAC-SIV gp120 prime boost vaccination strategy on peripheral and mucosal ILCs using C57BL/6
mice. Next, I will determine whether the ALVAC-HIV gp120/ alum prime-boost vaccination,
combined with augmented mucosal immunity by modulating ILC3 function via interacting with Aryl
hydrocarbon receptor (AhR) of ILC3 in the gut can enhance the protection against HIV infection
using humanized BLT mice. The results of this study will enhance our understanding of the
interplay between innate and adaptive responses in systemic and mucosal sites during HIV
vaccine. I envision that the combination of a moderately protective vaccine with enhanced mucosal
immunity via modulating NK/ILC3 by interacting with AhR will be recognized as a novel HIV
preventive vaccine approach. These results will lead ultimately to the development of a protective
HIV vaccine strategy for humans.
项目总结
项目成果
期刊论文数量(0)
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