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

描述（由申请人提供）：髓源性抑制细胞（MDSC）是最近表征的在癌症、感染、炎症和创伤期间扩增的细胞群。MDSC通过多种机制显示出显著的抑制T细胞介导的免疫的能力，所述机制包括产生辅酶I酶1、活性氧、一氧化氮和诱导调节性T细胞。MDSC代表了一种重要的调节反馈免疫机制，可在各种疾病的背景下预防过度的慢性炎症。HIV-1感染的特征是CD 4+和CD 8 + T细胞的慢性活化和快速更新。最近获得的证据表明，HIV-1感染与胃肠道粘膜组织中的慢性炎症和微生物产物易位到系统隔室中，在那里它们促进T细胞活化有关。活化驱动的CD 4 + T细胞再生能力的耗尽最终导致CD 4 + T细胞稳态的崩溃。慢性T细胞活化机制的精确表征对于理解HIV-1发病机制至关重要。预期与HIV-1感染相关的慢性免疫激活将导致MDSC群体的显著扩增，如在其他病毒和细菌感染中观察到的。令人惊讶的是，我们的初步数据表明，在HIV-1感染患者中，特别是未接受高效抗逆转录病毒治疗（HAART）的患者中，循环MDSC的频率显著降低。缺乏这一重要的调节群体，通常限制有害的免疫激活可能显着有助于不受控制的慢性炎症在全身腔室和肠粘膜组织和高发病率的自身免疫性疾病观察到的HIV-1感染的个人。我们将在三个具体目标中解决MDSC在HIV-1感染中的作用：1）确定MDSC在HIV-1感染个体的血液和肠组织中的频率是否降低; 2）确定MDSC是否可以直接感染HIV-1; 3）确定HIV-1感染患者的MDSC是否保留其免疫抑制活性。阐明MDSC在HIV-1感染中的作用可能有助于基于MDSC群体的受控扩增设计新的治疗策略，从而抑制HIV-1感染患者的慢性免疫激活。 公共卫生相关性：在本申请中，我们提出了一个新的观察结果，即HIV-1感染与髓源性抑制细胞（MDSC）的严重耗竭相关，并假设缺乏这种重要的免疫调节细胞群显著促进慢性免疫激活，导致CD 4 + T细胞的逐渐下降。慢性T细胞活化机制的精确表征是我们理解HIV-1发病机制的核心。阐明MDSC在HIV-1感染中的作用可能有助于基于MDSC群体的受控扩增设计新的治疗策略，从而抑制HIV-1感染患者的慢性免疫激活。

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.