GBV-C effects on CD4 activation and expansion

艾滋病毒疾病的进展在不同的人之间有很大的差异。尽管一些遗传或HIV蛋白因素具有 虽然已发现影响疾病进展的因素，但在大多数情况下，这些因素并不能解释艾滋病毒疾病进展缓慢的原因。我们 其他人发现感染GB病毒C(GBV-C)之间存在联系，GBV-C是一种常见的非致病性 人类黄病毒，以及在几个艾滋病毒感染者队列中延长存活时间。GBV-C感染也是 与减少母婴传播艾滋病毒有关。这些流行病学联系因在 体外研究表明，GBV-C感染CD4细胞通过调节宿主而有效地抑制HIV复制 细胞基因表达导致HIV进入减少，并促进CD4存活。 HIV导致定性和定量免疫功能障碍。尽管艾滋病毒直接杀死了CD4细胞，但 感染HIV的细胞数量不足以解释整体的CD4耗尽。精密机械(S) 目前还不完全清楚是哪种艾滋病病毒耗尽了CD4+T细胞。感染HIV本身引起的免疫激活 或其他微生物(例如，胃肠道细菌)，似乎是CD_4耗竭的关键。最近的数据发现，GBV-C感染 抑制体内和体外的CD4和CD8T细胞的激活，提示GBV-C可能影响这一疾病的HIV 举止。此外，在接受疫苗治疗的人中，GBV-C感染与CD4缺乏扩张有关 重组白介素2疗法(rIL-2)：一项多中心的盲法前瞻性试验。尽管这项研究规模很小，而且有些人 数据缺失，结果令人震惊。如果在更大的队列中得到确认，GBV-C感染将是一个关键 对rIL-2治疗和潜在的其他免疫调节试验的解释存在差异。 我们假设GBV-C与IL-2相互作用，可能是通过IL-2受体抑制T细胞的激活 和扩散，导致艾滋病毒疾病进展延缓。为了检验这一假设，我们提出了三个目标。第一, 我们将在更大的队列(ESPRIT)中确认我们的初步流行病学发现。其次，我们将考察其效果 GBV-C对HIV感染者和非感染者T细胞活化和增殖的影响 与IL-2活化的关系。最后，我们将表征GBV-C蛋白(S)和参与细胞的蛋白结构域 相互作用在体外抑制T细胞的激活。了解延迟HIV疾病的因素对于 了解HIV感染中的疾病变异性，并确定CD4细胞 在艾滋病毒感染期间保存的病毒可能被用来确定基于细胞的艾滋病毒治疗的新方法。

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.