Mechanisms of Natural Killer Cell Clearance of SIV from Lymphoid Follicles

淋巴滤泡自然杀伤细胞清除 SIV 的机制

基本信息

批准号：
10529270
负责人：
Roger Keith Reeves
金额：
$ 40.82万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10529270
关键词：
Acute Adherence African African Green Monkey Anatomy Autopsy B-Lymphocytes BLR1 gene Blood CD4 Positive T Lymphocytes Cell physiology Cells Cercocebus atys Chronic DNA Methylation Data Development Disease Disease Progression Early Mobilizations Early treatment Epidemic Evolution Exhibits Face Failure Flow Cytometry Frequencies Future Gut Mucosa HIV HIV-1 HIV/SIV vaccine Human Immunotherapeutic agent Impairment Infection Inflammation Inflammatory Interleukin-15 Left Lentivirus Infections Ligands Lymphoid Follicle Lymphoid Tissue Macaca Macaca mulatta Mediating Medicine Modeling Monkeys Morbidity - disease rate Natural Killer Cells Nature Pathogenesis Pathogenicity Patients Peptides Plasma Population RNA Regimen Research Rest Role SIV Signal Transduction Stains T-Lymphocyte Subsets Techniques Testing Tissues Vaccines Viral Viral Load result Viral reservoir Viremia Virus Virus Replication Work antiretroviral therapy cell killing cost cytotoxic cytotoxic CD8 T cells dimensional analysis exhaustion genome analysis immune activation in vivo innovation longitudinal analysis lymph nodes memory CD4 T lymphocyte nonhuman primate novel novel therapeutics purge response secondary lymphoid organ trafficking transcriptomics viral RNA

项目摘要

Despite efficient suppression of plasma viremia in HIV-infected patients on cART, replication competent virus is still recoverable from a variety of anatomic sites. A major reservoir of HIV and pathogenic SIV infection in rhesus macaques (RM) are lymph node follicles (via replication in TFH cells and viral trapping by FDC) that generally prohibit access to cytotoxic CD8+ T cells. Interestingly, nonpathogenic SIV infection of African green monkeys (AGM) exhibits high viral loads in blood and the gut mucosae, but lacks virus in lymphoid follicles. Natural killer (NK) cells provide rapid early responses to HIV/SIV infections and contribute substantially to disease modulation and vaccine protection, but the underlying mechanisms for NK cell surveillance and modulation of HIV/SIV reservoirs is unclear. Our recent research indicates that SIV can be effectively cleared from lymphoid follicles in nonpathogenic AGM but not pathogenic RM hosts and is dependent on an IL-15- dependent redistribution of NK cells to lymph node follicles and increased CXCR5 expression on AGM NK (Huot et al. Nature Medicine 2017). In this innovative proposal we will utilize three SIV-infected nonhuman primate models to test the central hypothesis that NK cells critically contribute to the reduction of SIV reservoirs. Specifically we will: (1) Determine mechanisms associated with NK cell-mediated control of SIV reservoirs; and (2) Determine mechanisms associated with NK cell failure to control SIV reservoirs in lymph nodes and associated pathogenesis. Application of these data could contribute substantially to future HIV/SIV vaccines, immunotherapeutics, or reservoir purging strategies that harness the potent antiviral potential of NK cells.

尽管在CART上有效抑制了HIV感染患者血浆病毒血症，但复制能力胜任病毒仍然可以从各种解剖部位回收。 HIV和致病性SIV感染的主要库在恒河猴（RM）中，是淋巴结卵泡（通过TFH细胞中的复制和FDC的病毒诱捕）通常禁止进入细胞毒性CD8+ T细胞。有趣的是，非洲绿色的非致病SIV感染猴子（AGM）在血液和肠道粘膜中表现出高病毒载荷，但缺乏淋巴卵泡病毒。天然杀手（NK）细胞对艾滋病毒/SIV感染提供了快速的早期反应，并为疾病调节和疫苗保护，但NK细胞监测的潜在机制和 HIV/SIV储藏的调节尚不清楚。我们最近的研究表明，SIV可以有效地清除来自非人为AGM的淋巴卵泡，而不是致病性RM宿主，并且取决于IL-15-- NK细胞对淋巴结卵泡的依赖性重新分布，并增加了AGM NK上的CXCR5表达（Huot等人自然医学2017）。在这个创新的建议中，我们将利用三个SIV感染的非人类灵长类动物模型测试中心假设，即NK细胞严重促进SIV的减少水库。具体我们将：（1）确定与NK细胞介导的对照相关的机制 SIV水库；（2）确定与NK细胞失败控制SIV储层相关的机制在淋巴结和相关的发病机理中。这些数据的应用可能会大大贡献未来的艾滋病毒/SIV疫苗，免疫治疗药或储层清除策略，以利用有效的抗病毒 NK细胞的潜力。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Non-human Primate Determinants of Natural Killer Cells in Tissues at Steady-State and During Simian Immunodeficiency Virus Infection.

DOI：
10.3389/fimmu.2020.02134
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Huot N;Rascle P;Petitdemange C;Contreras V;Palgen JL;Stahl-Hennig C;Le Grand R;Beignon AS;Jacquelin B;Müller-Trutwin M
通讯作者：
Müller-Trutwin M

SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells.

DOI：
10.1038/s41590-023-01661-4
发表时间：
2023-12
期刊：
NATURE IMMUNOLOGY
影响因子：
30.5
作者：
Huot, Nicolas;Planchais, Cyril;Rosenbaum, Pierre;Contreras, Vanessa;Jacquelin, Beatrice;Petitdemange, Caroline;Lazzerini, Marie;Beaumont, Emma;Orta-Resendiz, Aurelio;Rey, Felix A.;Reeves, R. Keith;Le Grand, Roger;Mouquet, Hugo;Mueller-Trutwin, Michaela
通讯作者：
Mueller-Trutwin, Michaela

NK-B cell cross talk induces CXCR5 expression on natural killer cells.

DOI：
10.1016/j.isci.2021.103109
发表时间：
2021-10-22
期刊：
iScience
影响因子：
5.8
作者：
Rascle P;Jacquelin B;Petitdemange C;Contreras V;Planchais C;Lazzerini M;Dereuddre-Bosquet N;Le Grand R;Mouquet H;Huot N;Müller-Trutwin M
通讯作者：
Müller-Trutwin M

Interests of the Non-Human Primate Models for HIV Cure Research.

DOI：
10.3390/vaccines9090958
发表时间：
2021-08-27
期刊：
Vaccines
影响因子：
7.8
作者：
Terrade G;Huot N;Petitdemange C;Lazzerini M;Orta Resendiz A;Jacquelin B;Müller-Trutwin M
通讯作者：
Müller-Trutwin M

Adaptive MHC-E restricted tissue-resident NK cells are associated with persistent low antigen load in alveolar macrophages after SARS-CoV-2 infection.