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艾滋病毒感染中免疫缺陷的主要驱动因素，可预测进展为艾滋病（Mellors等人，1995年）。也影响疾病进展克里思的免疫系统的关键特征是免疫激活;事实上，它是已知的CD 4+损失和AIDS时间的最强预测因子（Liu et al.，1997; Giorgi等人，1999; Deeks等人，2004年）。非特异性免疫激活是慢性HIV感染的标志;其重要性通过在SIV的天然宿主和具有高病毒载量但几乎没有免疫激活的罕见HIV感染的人中缺乏疾病进展而突出（Silvestri等人，2003; Choudhary等人，2007），说明解除病毒复制和免疫活化可以防止疾病进展。免疫活化的两种主要表现是活化标志物在T细胞上的表达和增加的T细胞更新（Hellerstein et al.，1999年）。在组织效应位点处的表达CCR 5的CD 4+效应记忆（TEM）细胞是HIV的主要靶标，并且由于病毒细胞溶解和活化诱导的细胞凋亡两者而寿命短（Finkel等人，1995年）。这些细胞很容易被naove和中央记忆（TCM）前体所取代。从SIV感染的猕猴的研究中已经获得了对TCM-TEM平衡的动力学的重要见解，其表明慢性免疫活化驱动CD 4 + TCM的分化以替代组织中耗尽的CD 4 + TEM，并且这种逐渐的损失最终耗尽TCM资源并导致疾病（Okoye et al.，2007年）。重要的是，在感染和疫苗接种的猕猴模型中，保留的CD 4 + TCM与较低的病毒载量和较长的存活期相关（Letvin et al.，2006; Karlsson等人，2007; Sun等人，2007; Mason等人，2008年）。该项目的总体目标是研究CD 4+记忆细胞亚群，特别是CD 4 + 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。我们推测，免疫激活驱动的CD 4+中枢记忆细胞耗竭影响HIV感染的疾病进展克里思。我们进一步假设感染前的免疫激活可能影响HIV易感性，感染前的CD 4+中央记忆细胞数量影响疾病进展。我们有一个独特的未经治疗的HIV-1 C亚型感染者队列，他们在感染前、急性感染期间接受了监测，并在慢性感染过程中接受了纵向随访。我们建议监测（1）免疫激活水平和（2）CD 4+记忆亚群动态，以阐明HIV感染中疾病进展的机制。目前的艾滋病毒治疗是针对抑制病毒。更好地了解对受影响器官（免疫系统）造成的损害以及它如何影响疾病进展可能会导致新的免疫治疗靶点。限制免疫激活和保护CD 4+中央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多万南非人感染，约占人口的12%。更好地了解影响艾滋病发展时间的免疫学和病毒机制可能会导致针对受损免疫系统的新疗法的开发，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.