Insulin-like growth factor axis influence on HIV and HPV pathogenesis in women

这项流行病学研究将考察胰岛素样生长因子(IGF)轴对 艾滋病毒和人乳头瘤病毒(HPV)这两种性传播病毒的发病机制。最近的数据表明 IGF轴通过对细胞增殖和存活的影响在宿主免疫中发挥作用，促使 推测它可能还会影响艾滋病毒疾病的进展速度。胰岛素样生长因子-I，一种具有促有丝分裂/抗凋亡作用的激素 在动物模型中，活动可以增加淋巴细胞数量，甚至可以诱导胸腺再生 被FIV感染的猫。相反，主要的IGF结合蛋白(IGFBP)，IGFBP-3，既有间接的(隔离) IGF-I)和直接(IGF-I不依赖)抗有丝分裂/促凋亡活性，并被假设为加速HIV 疾病。然而，几乎没有人类数据。我们仅使用基线样本进行了初步调查 来自女性S机构间艾滋病毒研究，一个持续的艾滋病毒阳性(N=2,793)和艾滋病毒阴性的队列 (n=975)妇女，1994年开始。发生的临床艾滋病(N=101例)与？IGFBP- 3(HR=2.7；1.3-5.4)在广泛使用HAART之前获得的数据/样本(HAART前)[再版1] -与IGFBP-3一致，S提出了对免疫系统的抗有丝分裂/促凋亡作用。该协会 患有艾滋病的IGF-I也在预期的方向上，尽管不显著(HR=0.64；0.35-1.18)，两者都 ？IGFBP-3(P趋势=0.02)和？IGF-I(P趋势=0.02)与CD4+T细胞的快速下降有关。的作用 对137例HIV阴性妇女进行了HPV自然病史中IGF轴的研究。致癌性HPV持续存在 关联到什么？IGF-I/IGFBP-3比值(HR=7.1；1.8~25)，而？IGFBP-3与极低的风险相关 致癌性HPV阳性宫颈肿瘤(HR=0.07；0.01-0.66)；大多数其他结果无显著意义，但在 预期方向-与胰岛素样生长因子轴一致？S对其他肿瘤和最近横断面的影响 宫颈肿瘤的研究。这些前瞻性的试点数据具有明确的临床意义。对于艾滋病毒，他们暗示 IGF轴可能被用作减缓艾滋病毒疾病治疗的靶点(将时间延长到 需要使用HAART)。如果在目前的研究中，我们在使用HAART的女性身上发现了类似的结果，它可能会 建议在HAART期间也以IGF轴为靶点。同样，对于HPV，我们的数据表明IGF轴可能 具有尚未开发的治疗/预防疾病的潜力。因此，该项目值得注意的是，它具有开放的潜力 流行病学和临床调查的几个新领域。根据这项拨款，我们将首次研究 使用HAART的妇女；在连续的研究访问中重复检测IGF-I和IGFBP-3，以仔细 确定IGF-I和IGFBP-3暴露的特征；研究其他IGF轴相关成分，包括IGF-II，FREE (生物活性)IGF-I和C-肽。这笔赠款还将大大增加每个端点的病例数量。 具体目的是研究IGF轴在以下方面的作用：(1)不使用胰岛素样生长因子轴的妇女的艾滋病毒疾病进展 HAART(根据HAART时代之前获得的样本/数据)；(2)#年与艾滋病有关的死亡风险 使用HAART的妇女；和(3)HIV阳性和阴性妇女致癌HPV的自然病史。

This epidemiologic study will examine the influence of the insulin-like growth factor (IGF)-axis on the pathogenesis of HIV and human papillomavirus (HPV), two sexually transmitted viruses. Recent data suggest that the IGF-axis plays a role in host immunity through its effects on cell proliferation and survival, prompting speculation that it might also affect the rate of HIV disease progression. IGF-I, a hormone with mitogenic/antiapoptotic activity can, in animal models, increase lymphocyte count, and even induce thymic regeneration in FIV infected cats. In contrast, the major IGF binding protein (IGFBP), IGFBP-3, has both indirect (sequestering IGF-I) and direct (IGF-I independent) anti-mitotic/pro-apoptotic activity, and is hypothesized to accelerate HIV disease. However, there is little human data. We conducted a pilot investigation using only baseline specimens from the Women¿s Interagency HIV Study (WIHS), an ongoing cohort of HIV-positive (N=2,793) and HIVnegative (N=975) women, initiated in 1994. Incident clinical AIDS (N=101 cases) was associated with ? IGFBP- 3 (HR=2.7;1.3-5.4) in data/specimens obtained prior to the widespread use of HAART (pre-HAART) [reprint 1] - consistent with IGFBP-3¿s proposed anti-mitotic/pro-apoptotic effects on the immune system. The association of IGF-I with AIDS was also in the expected direction, albeit, non-significant (HR=0.64;0.35-1.18), and both ? IGFBP-3 (Ptrend=0.02) and ? IGF-I (Ptrend=0.02) were associated with rapid CD4+ T-cell decline. The role of the IGF-axis in HPV natural history was studied in 137 HIV-negative women. Persistence of oncogenic HPV was associated with ? IGF-I/IGFBP-3 ratio (HR=7.1;1.8-25), while ? IGFBP-3 was associated with very low risk of oncogenic HPV-positive cervical neoplasia (HR= 0.07; 0.01-0.66); most other results were non-significant but in the expected direction - consistent with the IGF-axis¿s effects on other tumors and recent cross-sectional studies of cervical neoplasia. These prospective pilot data have clear clinical implications. For HIV, they imply that the IGF-axis might be exploited as a target for therapies to slow HIV disease (lengthening the time until HAART use becomes needed). If in the current study we find similar results in women using HAART, it could suggest also targeting the IGF-axis during HAART. Similarly, for HPV, our data suggest that the IGF-axis may have untapped potential to treat/prevent disease. The project is notable, therefore, for having potential to open several new areas of epidemiologic and clinical investigation. Under this grant we will for the first time study women using HAART; conduct repeated testing of IGF-I and IGFBP-3 at sequential study visits to carefully characterize IGF-I and IGFBP-3 exposure; study additional IGF-axis related components, including IGF-II, free (bioactive) IGF-I, and C-peptide. This grant will also greatly increase the number of cases for each endpoint. The Specific Aims are to study the role of the IGF-axis in: (1) HIV disease progression in women not using HAART (based on specimens/data obtained prior to the HAART era); (2) The risk of AIDS related death in women using HAART; and (3) The natural history of oncogenic HPV in HIV-positive and -negative women.