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

 描述（由申请方提供）：尽管接受cART治疗的HIV感染患者的血浆病毒血症得到有效抑制，但具有复制能力的病毒仍可从各种解剖部位回收，最明显的是静止记忆CD 4 + T淋巴细胞。尽管经验证据表明潜伏的HIV存在于整个口腔粘膜中，但口腔中感染细胞的全谱是不确定的，并且这些感染细胞的独特解剖结构的贡献是不确定的。 组织到全身性病毒库的作用是未知的。除了是HIV/SIV的潜在储存库之外，口腔是广泛的正常良性病原体的家园，这些病原体在合并感染期间诱导的免疫抑制是合并症的主要来源。虽然机会性病毒出现的潜在机制尚不完全清楚，但即使成功的ARV治疗，HIV疾病的口腔并发症也很普遍。 自然杀伤（NK）细胞对HIV/SIV感染提供快速的早期反应，并对疾病调节和疫苗保护做出重大贡献。传统上，NK细胞被认为是先天免疫的非特异性成分，但最近在小鼠中的研究表明，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高等灵长类动物中特异性针对HIV和SIV抗原的NK细胞记忆的证据（Reeves等人，Nat Imm，2015）。在这个创新的建议，我们将利用SIV共感染的猕猴模型来测试中心的假设，即NK细胞分布在整个口腔粘膜是一个共同的关键组成部分调制水库的SIV和机会性病毒感染。具体来说，我们将：（1）定义和量化SIV水库在 cART期间的口腔粘膜;（2）评价天然和抗原特异性NK细胞调节SIV复制和口腔粘膜中储库接种的机制;（3）探索NK细胞耗竭对SIV储库和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，免疫治疗剂或利用NK细胞强大的抗病毒潜力的储库清除策略。

 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.