Depletion of myeloid-derived suppressor cells (MDSCs) in HIV-1-infection

描述(申请人提供)：髓系来源的抑制细胞(MDSCs)是一种最近表征的细胞群体，在癌症、感染、炎症和创伤期间扩张。MDSCs通过多种机制抑制T细胞免疫，包括产生精氨酸酶1、活性氧、一氧化氮和诱导调节性T细胞。MDSCs代表了一种重要的调节反馈免疫机制，可防止在各种疾病背景下过度的慢性炎症。HIV-1感染的特点是CD4+和CD8+T细胞的慢性激活和快速更新。最近获得的证据表明，HIV-1感染与胃肠道粘膜组织的慢性炎症和微生物产物转移到全身隔室有关，在那里它们有助于T细胞的激活。活化驱动的CD4+T细胞再生能力衰竭最终导致CD4+T细胞动态平衡的崩溃。准确描述慢性T细胞激活的机制对于理解HIV-1的发病机制至关重要。正如在其他病毒和细菌感染中观察到的那样，预期与艾滋病毒-1感染相关的慢性免疫激活将导致MDSC种群的显着扩大。令人惊讶的是，我们的初步数据显示，HIV-1感染患者，特别是没有接受高效抗逆转录病毒治疗(HAART)的患者，循环中MDSCs的频率显著降低。缺乏这种重要的调节群体，通常限制有害的免疫激活，可能会显著导致全身隔室和肠道粘膜组织中的慢性炎症失控，并导致在HIV-1感染者中观察到的自身免疫性疾病的高发病率。我们将从三个具体目标探讨MDSCs在HIV-1感染中的作用：1)确定HIV-1感染者血液和肠道组织中MDSCs的频率是否减少；2)确定MDSCs是否可以直接感染HIV-1；以及3)确定HIV-1感染者中的MDSCs是否保持其免疫抑制活性。阐明MDSC在HIV-1感染中的作用可能有助于设计新的治疗策略，其基础是控制MDSC群体的扩张，从而抑制HIV-1感染者的慢性免疫激活。 公共卫生相关性：在这项应用中，我们提出了一个新的观察结果，即HIV-1感染与髓系来源的抑制细胞(MDSCs)的严重耗尽有关，并假设这一重要免疫调节群体的缺失显著促进了慢性免疫激活，导致CD4+T细胞逐渐下降。准确描述慢性T细胞激活的机制对于我们理解HIV-1的发病机制是至关重要的。阐明MDSC在HIV-1感染中的作用可能有助于设计新的治疗策略，其基础是控制MDSC群体的扩张，从而抑制HIV-1感染者的慢性免疫激活。

DESCRIPTION (provided by applicant): Myeloid-derived suppressor cells (MDSCs) is a recently characterized population of cells that expands during cancer, infection, inflammation, and trauma. MDSCs display a remarkable ability to suppress T cell-mediated immunity by multiple mechanisms including production of arginase 1, reactive oxygen species, nitric oxide, and induction of regulatory T cells. MDSCs represent an important regulatory feedback immune mechanism preventing exaggerated chronic inflammation in the context of various diseases. HIV-1 infection is characterized by chronic activation and rapid turnover of CD4+ and CD8+ T cells. Recently obtained evidence suggests that HIV-1 infection is associated with chronic inflammation in the gastrointestinal mucosal tissue and a translocation of microbial products to the systemic compartment where they contribute to T cell activation. Activation-driven exhaustion of CD4+ T cell regenerative capability eventually leads to the collapse of CD4+ T cell homeostasis. Precise characterization of the mechanisms underlying chronic T cell activation is central to the understanding of HIV-1 pathogenesis. It would be expected that chronic immune activation associated with HIV-1 infection would result in a significant expansion of MDSC population as observed in other viral and bacterial infections. Surprisingly, our preliminary data demonstrate that the frequency of circulating MDSCs is significantly reduced in HIV-1-infected patients, particularly patients not treated with highly active anti-retroviral therapy (HAART). Absence of this important regulatory population that normally restricts harmful immune activation may significantly contribute to the uncontrolled chronic inflammation in the systemic compartment and intestinal mucosal tissue and to the high incidence of autoimmune disorders observed in HIV-1-infected individuals. We will address the role of MDSCs in HIV-1 infection in three specific aims: 1) Determine whether the frequency of MDSCs is reduced in the blood and intestinal tissue of HIV-1-infected individuals; 2) Determine whether MDSCs can be directly infected with HIV-1; and 3) Determine whether MDSCs in HIV-1- infected patients preserve their immunosuppressive activity. Elucidation of the role of MDSCs in HIV-1 infection may be instrumental in the design of novel therapeutic strategies based on controlled expansion of MDSC population resulting in a suppression of chronic immune activation in HIV-1-infected patients. PUBLIC HEALTH RELEVANCE: In this application we present a novel observation that HIV-1 infection is associated with a severe depletion of myeloid-derived suppressor cells (MDSCs) and hypothesize that the absence of this important immunoregulatory population significantly contributes to the chronic immune activation resulting in the gradual decline of CD4+ T cells. Precise characterization of mechanisms underlying chronic T cell activation is central to our understanding of HIV-1 pathogenesis. Elucidation of the role of MDSCs in HIV-1 infection may be instrumental in the design of novel therapeutic strategies based on controlled expansion of MDSC population resulting in a suppression of chronic immune activation in HIV-1-infected patients.