GBV-C effects on CD4 activation and expansion

艾滋病毒疾病的进展在个体之间差异很大。尽管一些遗传或HIV蛋白质因素 虽然已经确定了影响疾病进展的因素，但这些因素并不能解释大多数情况下HIV疾病进展缓慢的原因。我们 和其他人发现感染与GB病毒C（GBV-C）感染，一种常见的非致病性， 人黄病毒，并延长了几个艾滋病毒感染者的生存期。GBV-C感染也是 与减少母婴艾滋病毒传播有关。这些流行病学的联系得到加强， 体外研究表明，GBV-C感染CD 4细胞通过调节宿主细胞， 细胞基因表达导致HIV进入减少并促进CD 4存活。 HIV导致定性和定量免疫功能障碍。虽然艾滋病毒直接杀死CD 4细胞， 感染HIV的细胞数量不足以解释总体CD 4耗竭。精确的机制， 艾滋病病毒消耗CD 4 + T细胞是不完全了解。HIV本身感染诱导的免疫激活 或其他微生物（例如GI细菌），似乎对CD 4耗竭至关重要。最近的数据发现，GBV-C感染 在体内和体外抑制CD 4和CD 8 T细胞活化，表明GBV-C可能在这种情况下影响HIV疾病。 方式此外，GBV-C感染与接受疫苗的人中CD 4缺乏扩张有关 重组IL-2治疗（rIL-2）的盲法、前瞻性、多中心试验。虽然这项研究规模很小， 数据缺失的情况下，结果是惊人的。如果在更大的队列中得到证实，GBV-C感染将是一个关键的 在rIL-2治疗和潜在的其他免疫调节试验的解释中是可变的。 我们假设GBV-C与IL-2相互作用，可能通过IL-2受体抑制T细胞活化 和增殖，导致HIV疾病进展延迟。为了验证这一假设，我们提出了三个目标。第一、 我们将在一个更大的队列（ESPRIT）中证实我们最初的流行病学发现。第二，我们会研究 GBV-C对HIV感染者和未感染者淋巴细胞中T细胞活化和增殖的影响 与IL-2激活有关。最后，我们将表征GBV-C蛋白和参与细胞凋亡的蛋白结构域。 抑制体外T细胞活化的相互作用。了解延迟艾滋病毒感染的因素对于预防艾滋病至关重要。 了解艾滋病毒感染的疾病变异性，并确定CD 4细胞被感染的机制。 可以利用在HIV感染期间保存的细胞来鉴定基于细胞的HIV治疗的新方法。

HIV disease progression varies widely among individuals. Although some genetic or HIV protein factors have been identified that affect disease progression, these do not explain slow HIV disease progression in most cases. We and others found an association between infection with GB virus C (GBV-C) infection, a common, nonpathogenic human flavivirus, and prolonged survival in several cohorts of HIV-infected people. GBV-C infection is also associated with decreased maternal-fetal HIV transmission. These epidemiological associations are strengthened by in vitro studies demonstrating that GBV-C infection of CD4 cells potently inhibits HIV replication by modulating host cellular gene expression resulting in decreased HIV entry and facilitating CD4 survival. HIV leads to qualitative and quantitative immune dysfunction. Although HIV directly kills CD4 cells, the number of cells infected with HIV is insufficient to explain the overall CD4 depletion. The precise mechanism(s) by which HIV depletes CD4+ T cells is incompletely understood. Immune activation induced by infection with HIV itself or other microbes (e.g. GI bacteria), appears to be critical for CD4 depletion. Recent data found that GBV-C infection dampens CD4 and CD8 T cell activation in vivo and in vitro, suggesting that GBV-C may influence HIV disease in this manner. In addition, GBV-C infection was associated with a lack of CD4 expansion among people who received recombinant IL-2 therapy (rIL-2) in a blinded, prospective, multicenter trial. Although the study was small and some data were missing, the results were striking. If confirmed in larger cohorts, GBV-C infection would be a critical variable in the interpretation of rIL-2 therapy and potentially other immunomodulatory trials. We hypothesize that GBV-C interacts with IL-2, potentially via the IL-2 receptor to dampen T cell activation and proliferation, resulting in delayed HIV disease progression. To test this hypothesis we propose three aims. First, we will confirm our initial epidemiological findings in a larger cohort (ESPRIT). Secondly, we will examine the effect of GBV-C on changes in T cell activation and proliferation in lymphocytes from HIV-infected and uninfected people in relation to IL-2 activation. Finally, we will characterize the GBV-C protein(s) and protein domains involved in cellular interactions dampening T cell activation in vitro. Understanding factors that delay HIV disease is critical for understanding disease variability in HIV infection, and identification of the mechanisms by which CD4 cells are preserved during HIV infection may be exploited to identify novel approaches of cellular-based HIV therapeutics.