Project 1: Immunologic and Virologic Characterization of RhCMV/SIV Vaccine-Mediated SIV Replication Arrest Efficacy
项目 1:RhCMV/SIV 疫苗介导的 SIV 复制抑制功效的免疫学和病毒学特征
基本信息
- 批准号:10709013
- 负责人:
- 金额:$ 53.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-22 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAntigen-Presenting CellsAntigensAutologousAutopsyB-LymphocytesBiopsyBlood CellsCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCellsCellular Indexing of Transcriptomes and Epitopes by SequencingCharacteristicsClinicCytomegalovirusDNADataDisease remissionEquilibriumExtinctionGene ExpressionGene Expression ProfileGenetic TranscriptionGoalsHIVHIV vaccineImmuneImmune responseImmunityImmunologicsInfectionInterleukin-15LinkMacaca mulattaMajor Histocompatibility ComplexMediatingMononuclearMyelogenousNatural Killer CellsNatureOutcomeOutputPatternPeptidesPhasePlasmaPopulationPrimary InfectionProcessProductionRNAResidual stateResistanceResolutionRestRhesusSIVSignal TransductionSiteT cell receptor repertoire sequencingT cell responseT memory cellT-Cell DepletionT-Cell ReceptorTimeTissuesTranslationsVaccinatedVaccinationVaccine AntigenVaccinesViralViremiaVirionVirusVirus DiseasesVirus ReplicationWhole Bloodantiretroviral therapycell typeclinical translationcohorthigh dimensionalityimmunoregulationin vivoindexingmemory CD4 T lymphocytepre-clinicalpreventprophylacticresponsetranscriptome sequencingtranscriptomicsvectorvector induced
项目摘要
PROJECT 1 - PROJECT SUMMARY
A pre-clinical HIV vaccine approach based on strain 68-1 of rhesus cytomegalovirus expressing SIV antigens
(RhCMV/SIV) elicits cellular immune responses that stringently arrest replication and spread of primary SIV
infection in 59% of vaccinated rhesus macaques (RMs). The vast majority of these vaccine-protected RMs will
maintain this SIV replication arrest (a state of aviremia with replication-competent SIV in tissues) until virus
decays or is cleared to extinction over the subsequent 1-3 years. This pattern of immune-mediated viral
suppression has no prior precedent and although the precise virologic and immunological mechanisms
underpinning this phenomenon remain unknown, we have established that (a) replication arrest efficacy depends
on RhCMV/SIV elicitation of SIV-specific CD8+ T cells that target SIV peptides in the context of major
histocompatibility complex (MHC)-E rather than MHC-II or conventional MHC-Ia, and (b) that among RMs with
MHC-E-restricted CD8+ T cell responses, efficacy is predicted by a sustained whole blood transcriptomic
signature featuring IL-15 signaling. These data suggest that an innate immune/IL-15 signaling-facilitated, MHC-
E-restricted, SIV-specific CD8+ T cell response mediates/coordinate replication arrest efficacy and that the in
vivo functional outputs underlying this pattern efficacy are unique to this response and thus different from
functional outputs of other types of SIV-specific CD8+ T cell responses. This, in turn, suggests that detailed
functional comparison of the effective responses with other vaccine-elicited CD8+ T cell response types that fail
to mediate replication arrest efficacy (including MHC-Ia- and MHC-II-restricted responses by programmed
RhCMV/SIV and MHC-Ia-restricted responses by conventional prime-boost vaccination) will elucidate
differences that underlie the replication arrest outcome. Thus, in S.A.1 we will utilize T cell receptor (TCR)-
indexed single cell transcriptomics to identify cell-intrinsic transcriptional patterns that distinguish these SIV-
specific CD8+ T cell responses in late vaccine phase and, importantly. correlate with subsequent SIV challenge
outcome (replication arrest vs. progressive infection). In S.A.2, we will virologically characterize early replication
arrest, determining the tissue extent, cellular distribution and state of residual SIV (transcription, translation,
virion production) among 68-1 RhCMV/SIV vector-protected RM at necropsy. Our goal is to define the sites and
cells hosting replication arrest and whether it involves suppression of SIV gene expression and virion production
(analogous to deep latency) and/or an effect on target cells, rendering them resistant to viral infection. Finally, in
S.A.3, we will characterize the cellular response (both CD8+ T cells and accessory cell types) to arrested SIV
replication in RhCMV/SIV-protected RMs via bulk and single cell transcriptomics and spatial profiling in necropsy
tissues. Successful completion of these studies will further our understanding of the unique protection afforded
by CMV vectors and facilitate successful clinical translation of CMV-based vectors for a prophylactic HIV vaccine.
项目1 -项目概要
基于表达SIV抗原的恒河猴巨细胞病毒68-1株的HIV临床前疫苗研究
(RhCMV/SIV)增强细胞免疫应答,严格阻止原发性SIV的复制和传播
59%的接种疫苗的恒河猴(RM)感染。绝大多数疫苗保护的RM将
维持这种SIV复制停滞(组织中具有复制能力的SIV的一种病毒血症状态),
在随后的1-3年内腐烂或灭绝。这种免疫介导的病毒
抑制没有先例,尽管精确的病毒学和免疫学机制
这一现象的基础仍然未知,我们已经确定,(a)复制抑制功效取决于
对RhCMV/SIV诱导靶向SIV肽的SIV特异性CD 8 + T细胞的作用
组织相容性复合物(MHC)-E而不是MHC-II或常规MHC-Ia,和(B)在具有
MHC-E限制性CD 8 + T细胞应答,通过持续的全血转录组学预测疗效。
特征在于IL-15信号传导。这些数据表明,先天免疫/IL-15信号促进,MHC-
E-限制性SIV特异性CD 8 + T细胞应答介导/协调复制阻滞功效,
作为这种模式功效基础的体内功能输出对于这种响应是独特的,因此不同于
其他类型的SIV特异性CD 8 + T细胞应答的功能输出。这反过来又表明,
有效应答与其他疫苗诱导的CD 8 + T细胞应答类型的功能比较,
介导复制抑制功效(包括通过程序化的MHC-Ia-和MHC-II-限制性应答),
通过常规初免-加强免疫接种的RhCMV/SIV和MHC-Ia限制性应答)将阐明
这些差异是复制停滞结果的基础。因此,在S.A.1中,我们将利用T细胞受体(TCR)-
索引的单细胞转录组学,以确定区分这些SIV的细胞内在转录模式,
特异性CD 8 + T细胞应答,重要的是。与随后的SIV激发相关
结果(复制停滞vs.进行性感染)。在S.A.2中,我们将对早期复制进行病毒学表征
阻滞,确定残留SIV的组织范围、细胞分布和状态(转录,翻译,
在尸检时,68-1 RhCMV/SIV载体保护的RM中的病毒体产生)。我们的目标是定义网站,
宿主细胞复制停滞以及是否涉及抑制SIV基因表达和病毒体产生
(类似于深潜伏期)和/或对靶细胞的作用,使它们对病毒感染具有抗性。最后在
S.A.3,我们将表征对被抑制的SIV的细胞应答(CD 8 + T细胞和辅助细胞类型
在尸检中通过本体和单细胞转录组学和空间分析在RhCMV/SIV保护的RM中复制
组织中这些研究的成功完成将使我们进一步了解所提供的独特保护
通过CMV载体,并促进预防性HIV疫苗的基于CMV的载体的成功临床翻译。
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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Jonah B. Sacha其他文献
OP 2.1 CCR5 in HIV Prevention and Cure
- DOI:
10.1016/j.jve.2022.100149 - 发表时间:
2022-12-01 - 期刊:
- 影响因子:
- 作者:
Helen L. Wu;Gabriela M. Webb;Jonah B. Sacha - 通讯作者:
Jonah B. Sacha
Jonah B. Sacha的其他文献
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{{ truncateString('Jonah B. Sacha', 18)}}的其他基金
Project 1: Immunologic and Virologic Characterization of RhCMV/SIV Vaccine-Mediated SIV Replication Arrest Efficacy
项目 1:RhCMV/SIV 疫苗介导的 SIV 复制抑制功效的免疫学和病毒学特征
- 批准号:
10619302 - 财政年份:2022
- 资助金额:
$ 53.07万 - 项目类别:
AAV Delivered CCR5 Blockade for Prevention of Mother-to-Child HIV Transmission.
AAV 提供 CCR5 阻断以预防 HIV 母婴传播。
- 批准号:
10670864 - 财政年份:2022
- 资助金额:
$ 53.07万 - 项目类别:
A Solid-Phase, Long-Acting CCR5 Monoclonal Antibody for HIV Transmission
针对 HIV 传播的固相长效 CCR5 单克隆抗体
- 批准号:
10222531 - 财政年份:2020
- 资助金额:
$ 53.07万 - 项目类别:
Learning from the Ebola success: Can a mAb also save lives after yellow fever infection?
借鉴埃博拉病毒的成功经验:单克隆抗体也能拯救黄热病感染后的生命吗?
- 批准号:
10082044 - 财政年份:2020
- 资助金额:
$ 53.07万 - 项目类别:
A Solid-Phase, Long-Acting CCR5 Monoclonal Antibody for HIV Transmission
针对 HIV 传播的固相长效 CCR5 单克隆抗体
- 批准号:
10064937 - 财政年份:2020
- 资助金额:
$ 53.07万 - 项目类别:
A Solid-Phase, Long-Acting CCR5 Monoclonal Antibody for HIV Transmission
针对 HIV 传播的固相长效 CCR5 单克隆抗体
- 批准号:
10443716 - 财政年份:2020
- 资助金额:
$ 53.07万 - 项目类别:
A Solid-Phase, Long-Acting CCR5 Monoclonal Antibody for HIV Transmission
针对 HIV 传播的固相长效 CCR5 单克隆抗体
- 批准号:
10650749 - 财政年份:2020
- 资助金额:
$ 53.07万 - 项目类别:
An IL-15 superagonist approach to clear the latent viral reservoir
IL-15 超级激动剂清除潜伏病毒库的方法
- 批准号:
10083693 - 财政年份:2018
- 资助金额:
$ 53.07万 - 项目类别:
An IL-15 superagonist approach to clear the latent viral reservoir
IL-15 超级激动剂清除潜伏病毒库的方法
- 批准号:
10320407 - 财政年份:2018
- 资助金额:
$ 53.07万 - 项目类别:
An IL-15 superagonist approach to clear the latent viral reservoir
IL-15 超级激动剂清除潜伏病毒库的方法
- 批准号:
10065757 - 财政年份:2018
- 资助金额:
$ 53.07万 - 项目类别:
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