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(申请人提供)：尽管在CART上有效地抑制了HIV感染患者的血浆病毒血症，但具有复制能力的病毒仍然可以从各种解剖部位恢复，最显著的是静止记忆的CD4+T淋巴细胞。虽然经验证据表明潜伏的hiv病毒存在于整个口腔粘膜中，但口腔中感染细胞的全谱尚不确定，这些细胞的独特解剖结构所起的作用尚不明确。 组织对全身病毒库的作用尚不清楚。除了是HIV/SIV的潜在宿主外，口腔还是一系列通常是良性的病原体的家园，在联合感染期间，诱导的免疫抑制是共病的主要来源。虽然机会性病毒出现的潜在机制还不完全清楚，但即使成功地进行了ARV治疗，艾滋病毒疾病的口腔并发症也是普遍存在的。自然杀伤(NK)细胞对HIV/SIV感染提供快速的早期反应，并在疾病调节和疫苗保护方面做出重大贡献。传统上，NK细胞被认为是天然免疫的非特异性成分，但最近在小鼠身上的研究表明，NK细胞也可以表现出抗原特异性记忆的特征。我们现在还首次证明了在高等灵长类动物中有NK细胞记忆的证据，特别是针对HIV和SIV抗原(Reeves等人，NAT IMM，2015)。在这个创新的方案中，我们将利用SIV联合感染猕猴模型来检验中心假设，即分布在口腔粘膜中的NK细胞是调节SIV和机会性病毒感染储备库的共同关键成分。具体地说，我们将：(1)定义和量化 (2)评价天然和抗原特异性NK细胞对SIV复制的调节机制和口腔粘膜中的病毒接种；(3)探讨NK细胞耗竭对SIV病毒感染和重组人LCV和重组人巨细胞病毒混合感染的影响。这些数据的应用可能导致未来的HIV/SIV疫苗、免疫疗法或利用NK细胞强大的抗病毒潜力的水库清除策略。