Innate Lymphoid Cell Modulation of SIV Transmission and Pathogenesis

 描述（由申请方提供）：尽管进行了深入研究，但控制和预防HIV感染所需的免疫应答仍然未知。虽然针对HIV和SIV的有效适应性T和B细胞应答是建立的，但它们直到大规模病毒传播和CD 4 + T细胞损失已经发生之后才出现。HIV/SIV感染还破坏胃肠道粘膜的完整性，导致慢性免疫激活，从而推动疾病进展。我们实验室和其他实验室的最新数据已经确定了猕猴对应的3型粘膜限制性先天淋巴样细胞（ILC），可通过高表达NKp 44和ROR β t区分。虽然ILC在粘膜防御和体内平衡中发挥关键作用，但这些细胞的全部功能仍有待阐明，并且这些细胞是否可以对慢病毒产生抗病毒免疫应答仍不清楚，部分原因是这些细胞的特征仍然很差。有趣的是，ILC在SIV感染后很早就从胃肠道中耗尽，并且通常非溶细胞的ILC在感染期间显著上调细胞毒性功能。这可能表明病毒对ILC的破坏可能促进传播和疾病进展。在这项新的提案中，我们将通过利用新的抗NKp 44 ILC消耗抗体来解决这一新研究领域的主要缺陷。我们将评估NKp 44 + ILC调节肠道内稳态和免疫激活的总体假设，并且耗尽将加剧SIV的传播和传播。我们将用两个集中的特定目的来评估这一假设：（1）定义在正常恒河猴中施用抗NKp 44的动力学、活化和详细的免疫学效应;和（2）研究ILC耗竭对SIV传播、传播和攻毒后疾病的影响。

 DESCRIPTION (provided by applicant): Despite intensive investigation the immune responses necessary for control of, and protection against HIV infection remain unknown. While potent adaptive T and B cell responses are mounted against HIV and SIV, they do not emerge until after massive virus dissemination and CD4+ T cell loss has already occurred. HIV/SIV infections also break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation that drives disease progression. Recent data from our laboratory and others have identified the macaque counterpart to Type 3 mucosae-restricted innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORt. Although ILCs play key roles in mucosal defense and homeostasis, the full functional repertoires of these cells remain to be elucidated, and whether these cells could mount antiviral immune responses against lentiviruses remains unclear, in part because these cells remain very poorly characterized. Interestingly, ILCs are depleted very early from the gastrointestinal tract following SIV infection and ILCs, which are normally noncytolytic, dramatically upregulate cytotoxic functions during infection. This could suggest subversion of ILCs by the virus may facilitate transmission and disease progression. In this new proposal we will address major deficits to this new field of study by utilizing a new anti-NKp44 ILC-depleting antibody. We will evaluate the overarching hypothesis that NKp44+ ILCs modulate gut homeostasis and immune activation, and depletion will exacerbate SIV transmission and dissemination. We will evaluate this hypothesis with two focused Specific Aims: (1) Define the kinetics, activation, and detailed immunologic effects of anti-NKp44 administration in normal rhesus macaques; and (2) Investigate the effects of ILC depletion on SIV transmission, dissemination, and disease following challenge.