The role of CD4+ memory subsets and immune activation in HIV disease progression

描述（由申请人提供）：持续高水平的病毒是HIV感染中免疫缺陷的主要驱动因素，预示着艾滋病的发展（Mellors等，1995）。影响疾病进展速度的免疫系统的一个关键特征是免疫激活；事实上，它是已知的CD4+损失和艾滋病时间的最强预测因子（Liu et al., 1997; Giorgi et al., 1999; Deeks et al., 2004）。非特异性免疫激活是慢性艾滋病毒感染的一个标志；在SIV的自然宿主和具有高病毒载量但很少免疫激活的罕见hiv感染人类中，疾病没有进展，这突出了它的重要性（Silvestri等人，2003；Choudhary等人，2007），说明断开病毒复制和免疫激活可以预防疾病进展。免疫激活的两个主要表现是T细胞上激活标记物的表达和T细胞周转增加（Hellerstein et al., 1999）。组织效应位点表达ccr5的CD4+效应记忆（TEM）细胞是HIV的主要靶点，由于病毒细胞溶解和激活诱导的细胞凋亡，这些细胞寿命很短（Finkel et al., 1995）。这些细胞很容易被中央记忆（TCM）前体所取代。对siv感染的猕猴的研究获得了中医-TEM平衡动力学的重要见解，该研究表明，慢性免疫激活驱动CD4+中医分化，以取代组织中CD4+ TEM的耗尽，这种逐渐的损失最终耗尽中医资源并导致疾病（Okoye等，2007）。重要的是，在感染和接种疫苗的猕猴模型中，保存的CD4+ TCM与较低的病毒载量和较长的存活相关（Letvin等人，2006；Karlsson等人，2007；Sun等人，2007；Mason等人，2008）。本项目的总体目标是研究CD4+记忆细胞亚群，特别是CD4+ TCM，如何影响HIV感染的疾病进展，以及它们与免疫激活的关系。我们假设由免疫激活驱动的CD4+中枢记忆细胞耗竭影响HIV感染的疾病进展速度。我们进一步假设免疫激活预感染可能影响HIV易感性，CD4+中枢记忆细胞的数量预感染影响疾病进展。我们有一个独特的未经治疗的HIV-1亚型C感染个体队列，在感染前、急性感染期间进行监测，并在慢性感染过程中进行纵向跟踪。我们建议在该队列中监测(1)免疫激活水平和(2)CD4+记忆亚群动态，以阐明HIV感染疾病进展的机制。目前针对艾滋病毒的治疗旨在抑制病毒。更好地了解受影响器官（免疫系统）的损害及其如何影响疾病进展可能会导致新的免疫治疗靶点。限制免疫激活和保留CD4+中枢记忆细胞可能是可行的非病毒干预靶点。公共卫生相关性：南非是世界上艾滋病毒流行最严重的国家之一，有500多万南非人受到感染，约占人口的12%。更好地了解影响艾滋病发病时间的免疫和病毒机制可能导致开发针对受损免疫系统的新疗法，从而在开始抗逆转录病毒治疗之前延长无艾滋病生存时间。

DESCRIPTION (provided by applicant): Persistent high levels of virus are the primary driver of immunodeficiency in HIV infection, predicting progression to AIDS (Mellors et al., 1995). A key feature of the immune system that also affects the tempo of disease progression is immune activation; in fact, it is the strongest known predictor of CD4+ loss and time to AIDS (Liu et al., 1997; Giorgi et al., 1999; Deeks et al., 2004). Non-specific immune activation is a hallmark of chronic HIV infection; its importance is highlighted by lack of disease progression in natural hosts of SIV and rare HIV-infected humans that have high viral loads but little immune activation (Silvestri et al., 2003; Choudhary et al., 2007), illustrating that de-linking viral replication and immune activation can prevent disease progression. Two major manifestations of immune activation are expression of activation markers on T cells, and increased T cell turnover (Hellerstein et al., 1999). CCR5-expressing CD4+ effector memory (TEM) cells at tissue effector sites are the main target of HIV, and are short-lived due to both viral cytolysis and activation-induced apoptosis (Finkel et al., 1995). These cells are easily replaced by naove and central memory (TCM) precursors. Important insights into the dynamics of the TCM-TEM balance have been gained from studies in SIV-infected macaques, which suggest that chronic immune activation drives differentiation of CD4+ TCM to replace CD4+ TEM depleted in tissues, and this gradual loss eventually exhausts TCM resources and leads to disease (Okoye et al., 2007). Importantly, preserved CD4+ TCM were a correlate of lower viral loads and longer survival in macaque models of infection and vaccination (Letvin et al., 2006; Karlsson et al., 2007; Sun et al., 2007; Mason et al., 2008). The overall aim of this project is to investigate how CD4+ memory cell subsets, particularly CD4+ TCM, impact on disease progression in HIV infection, and their relationship with immune activation. We hypothesize that CD4+ central memory cell depletion driven by immune activation influences the tempo of disease progression in HIV infection. We further hypothesize that immune activation pre-infection may influence HIV susceptibility and the number of CD4+ central memory cells pre-infection influences disease progression. We have a unique cohort of untreated HIV-1 subtype C infected individuals that have been monitored pre-infection, during acute infection and are being followed longitudinally over the course of chronic infection. We propose to monitor (1) levels of immune activation and (2) CD4+ memory subset dynamics in this cohort to elucidate mechanisms of disease progression in HIV infection. Current therapy for HIV is directed at inhibiting the virus. A better understanding of the damage caused to the affected organ (the immune system) and how it influences disease progression may lead to new immune therapeutic targets. Limiting immune activation and preserving CD4+ central memory cells may represent viable non-viral targets for intervention. PUBLIC HEALTH RELEVANCE: South Africa has one of the largest HIV epidemics in the world, with over 5 million South Africans infected, representing approximately 12 % of the population. A better understanding of the immunological and viral mechanisms that influence the time till development of AIDS may lead to the development of new therapies targeting the damaged immune system, leading to longer AIDS-free survival times prior to initiation of antiretroviral therapy.