Mechanisms of innate modulation of SIV reservoirs and opportunistic disease in the oral cavity

SIV 储库的先天调节机制和口腔机会性疾病

• 批准号: 9117095
• 负责人: Roger Keith Reeves
• 金额: $ 72.38万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117095
• 关键词: Adherence; Anatomy; Antigens; Antiviral Agents; B-Lymphocytes; Benign; Biopsy; CD4 Positive T Lymphocytes; Candidiasis; Cells; Chronic; Comorbidity; Cytolysis; Cytomegalovirus; DNA; Data; Development; Diffuse; Disease; Effector Cell; Epidemic; Epstein-Barr Virus Infections; Face; Future; Gingivitis; Goals; HIV; HIV-1; HIV/SIV vaccine; Hairy Leukoplakia; Herpesviridae; Home environment; Human Herpesvirus 8; Immune response; Immune system; Immunosuppression; Immunotherapeutic agent; Infection; Infiltration; Kinetics; Laboratories; Lead; Life; Ligands; Lymphoid Tissue; Macaca; Macaca mulatta; Maintenance; Mediating; Memory; Methods; Modeling; Morbidity - disease rate; Mouth Diseases; Mouth Neoplasms; Mus; Natural Immunity; Natural Killer Cells; Opportunistic Infections; Oral; Oral cavity; Oral mucous membrane structure; Patients; Periodontitis; Plasma; Primates; Property; RNA; Regimen; Rest; Role; SIV; Site; Source; Testing; Therapeutic; Time; Tissues; Tonsil; Ulcer; Up-Regulation; Vaccines; Viral reservoir; Viremia; Virus; Virus Diseases; Widespread Disease; Work; antiretroviral therapy; cancer cell; co-infection; cost; exhaust; gastrointestinal; immune activation; in vivo; innovation; lymph nodes; memory CD4 T lymphocyte; mucosal site; neoplastic cell; novel; oral HIV; oral cavity epithelium; pathogen; public health relevance; purge; response

 DESCRIPTION (provided by applicant): Despite efficient suppression of plasma viremia in HIV-infected patients on cART, replication competent virus is still recoverable from a variety of anatomic sites and most notably quiescent memory CD4+ T lymphocytes. Although empirical evidence suggests latent HIV is present throughout the oral mucosae, the full spectrum of infected cells in the oral cavity is undefined, and the contribution of the unique anatomy of these tissues to the systemic viral reservoir is unknown. In addition to being a potential reservoir for HIV/SIV, the oral cavity is home to a wide range of normally benign pathogens that during co-infection induced immunosuppression are major sources of co-morbidities. Although the underlying mechanisms for emergence of opportunistic viruses are not entirely clear, oral complications of HIV disease are widespread even with successful ARV therapy. Natural killer (NK) cells provide rapid early responses to HIV/SIV infections and contribute substantially to disease modulation and vaccine protection. Traditionally, NK cells have been considered to be nonspecific components of innate immunity, but recent studies in mice have shown that NK cells can also demonstrate features of antigen-specific memory. We also now demonstrate for the first time evidence of NK cell memory in higher primates specifically against HIV and SIV antigens (Reeves et al., Nat Imm, 2015). In this innovative proposal we will utilize the SIV-co-infected macaque model to test the central hypothesis that NK cells distributed throughout the oral mucosae are a common critical component for modulation of reservoirs of SIV and opportunistic viral infections. Specifically we will: (1) Define and quantify SIV reservoirs in the oral mucosa during cART; (2) Evaluate mechanisms of innate and antigen-specific NK cell modulation of SIV replication and reservoir seeding in the oral mucosae; and (3) Explore the effects of NK cell depletion on SIV reservoirs and rhLCV and rhCMV co-infections. Application of these data could lead to future HIV/SIV vaccines, immunotherapeutics, or reservoir purging strategies that harness the potent antiviral potential of NK cells.

 描述（由申请人提供）：尽管 cART 有效抑制了 HIV 感染患者的血浆病毒血症，但仍可从各种解剖部位尤其是静态记忆 CD4+ T 淋巴细胞中恢复具有复制能力的病毒，尽管经验证据表明存在潜在的 HIV。在整个口腔粘膜中，口腔中感染细胞的全谱尚不清楚，并且这些细胞的独特解剖结构的贡献 口腔组织与全身病毒库之间的关系尚不清楚，口腔除了是 HIV/SIV 的潜在储存库之外，也是多种正常良性病原体的家园，这些病原体在共同感染引起的免疫抑制过程中是并发症的主要来源。机会性病毒出现的潜在机制尚不完全清楚，即使抗逆转录病毒治疗成功，HIV 疾病的口腔并发症也很普遍。自然杀伤 (NK) 细胞可以对 HIV/SIV 感染提供快速的早期反应，并为疾病调节和疫苗接种做出重大贡献。传统上，NK细胞被认为是先天免疫的非特异性成分，但最近对小鼠的研究表明，NK细胞还可以表现出抗原特异性记忆的特征，我们现在也首次证明了NK细胞记忆的证据。在高等灵长类动物中，特异性针对 HIV 和 SIV 抗原（Reeves 等人，Nat Imm，2015）。在这项创新提案中，我们将利用 SIV 共同感染的猕猴模型来测试 NK 细胞分布于整个体内的中心假设。口腔粘膜是调节 SIV 储存库和机会性病毒感染的常见关键组成部分，具体而言，我们将： (1) 定义和量化口腔粘膜中的 SIV 储存库。 cART 期间的口腔粘膜；(2) 评估口腔粘膜中 SIV 复制和储库播种的先天性和抗原特异性 NK 细胞调节机制；以及 (3) 探索 NK 细胞耗竭对 SIV 储库以及 rhLCV 和 rhCMV 共存的影响这些数据的应用可能会导致未来的 HIV/SIV 疫苗、免疫疗法或利用 NK 细胞强大抗病毒潜力的储库清除策略。