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

描述(由申请人提供)：持续的高水平病毒是艾滋病毒感染中免疫缺陷的主要驱动因素，预测进展为艾滋病(Mellors等人，1995年)。免疫系统的一个关键特征也会影响疾病进展的速度，那就是免疫激活；事实上，它是已知的最强的预测CD4+丢失和艾滋病发病时间的指标(Liu等人，1997年；Giorgi等人，1999年；Deek等人，2004年)。非特异性免疫激活是慢性艾滋病毒感染的一个标志；在SIV的自然宿主和病毒载量高但免疫激活很少的罕见艾滋病毒感染者中，疾病没有进展就突显了它的重要性(Silvestri等人，2003年；Choudhary等人，2007年)，这表明，将病毒复制和免疫激活分离可以防止疾病进展。免疫激活的两个主要表现是T细胞上激活标记的表达和T细胞周转率的增加(Hellerstein等人，1999)。在组织效应部位表达CCR5的CD4+效应记忆(TEM)细胞是HIV的主要靶点，由于病毒的细胞溶解和激活诱导的凋亡，这些细胞都是短暂的(Finkel等人，1995)。这些细胞很容易被NAOVE和中央记忆(Medics)前体取代。从对感染SIV的猕猴的研究中，我们获得了对中医药-透射电子显微镜平衡动态变化的重要见解，这些研究表明，慢性免疫激活推动了CD4+中医的分化，取代了组织中耗尽的CD4+透射电子显微镜，这种逐渐丧失的过程最终耗尽了中医药资源并导致疾病(Okoye等人，2007年)。重要的是，在感染和疫苗接种的猕猴模型中，保存的CD4+Tcm与较低的病毒载量和较长的生存期相关(Letvin等人，2006年；Karlsson等人，2007年；Sun等人，2007年；Mason等人，2008年)。这个项目的总体目标是研究CD4+记忆细胞亚群，特别是CD4+中医，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+中央记忆细胞枯竭影响艾滋病毒感染的疾病进展速度。我们进一步假设，感染前的免疫激活可能影响艾滋病毒的易感性，感染前的CD4+中央记忆细胞的数量影响疾病的进展。我们有一个独特的未经治疗的艾滋病毒-1 C亚型感染者队列，他们在感染前、急性感染期间接受监测，并在慢性感染过程中进行纵向跟踪。我们建议在这个队列中监测(1)免疫激活水平和(2)CD4+记忆亚群动态，以阐明HIV感染中疾病进展的机制。目前对艾滋病毒的治疗是针对抑制病毒的。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目标。限制免疫激活和保护CD4+中央记忆细胞可能是可行的非病毒干预靶点。与公共卫生相关：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，约占总人口的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.