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（由适用提供）：尽管在购物车中有效抑制了血浆病毒血症，但在卡车上感染了HIV的患者，但复制能力的病毒仍然可以从各种解剖部位，最著名的静态记忆CD4+ T淋巴细胞中得以回收。尽管经验证据表明在整个口腔粘膜中都存在潜在的HIV，但口腔中的全部感染细胞不确定，并且这些独特解剖学的贡献 全身病毒储层的组织尚不清楚。除了成为艾滋病毒/SIV的潜在储层外，口腔还具有广泛的良性病原体的家园，在共感染诱导的免疫抑制过程中，这些病原体是合并症的主要来源。尽管机会性病毒出现的基本机制尚不完全清楚，但即使成功进行了ARV疗法，艾滋病毒疾病的口腔并发症也很普遍。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做出了重大贡献。传统上，NK细胞被认为是先天免疫学的非特异性组成部分，但最近在小鼠中的研究表明，NK细胞还可以证明抗原特异性记忆的特征。现在，我们还证明了第一次针对HIV和SIV抗原的NK细胞记忆第一次证据（Reeves等人，Nat Imm，2015年）。在这项创新的建议中，我们将利用SIV-CO感染的猕猴模型来测试中心假设：NK细胞分布在整个口腔粘膜中是调节SIV和机会性病毒感染储层的常见关键成分。具体而言，我们将：（1）在 手推车期间的口腔粘膜； （2）评估口服粘膜中SIV复制和储层播种的先天和抗原特异性NK细胞调节机制； （3）探索NK细胞部署对SIV储层以及RHLCV和RHCMV共感染的影响。这些数据的应用可能会导致未来的HIV/SIV疫苗，免疫治疗药或储层清除策略，从而利用NK细胞的潜在抗病毒潜力。