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

胰岛素样生长因子轴对女性 HIV 和 HPV 发病机制的影响

• 批准号: 7644672
• 负责人: HOWARD D STRICKLER
• 金额: $ 48万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7644672
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adverse event; Affect; Animal Model; Antimitotic Agents; Apoptotic; Area; Biological Assay; Blood; C-Peptide; CD4 Positive T Lymphocytes; Cell Proliferation; Cervical; Cessation of life; Clinical; Clinical Trials; Cohort Analysis; Collaborations; Common Neoplasm; Cross-Sectional Studies; DNA; Data; Detection; Development; Diabetes Mellitus; Disease; Disease Progression; Effectiveness; End Point; Epidemiologic Studies; Exposure to; Feline Immunodeficiency Virus; Felis catus; Goals; Grant; Growth Factor; HIV; HIV Seropositivity; Hematopoietic stem cells; Highly Active Antiretroviral Therapy; Hormones; Human; Human Papillomavirus; IGF1 gene; Immune system; Immunity; Immunologics; Incidence; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Insulin-Like Growth Factor II; Insulin-Like Growth-Factor-Binding Proteins; Investigation; Lipodystrophy; Lymphocyte Count; Malignant Neoplasms; Measures; Mitotic; Natural History; Natural regeneration; Neoplasms; Numbers; Obesity; Oncogenic; Osteoporosis; Paper; Papillomavirus; Pathogenesis; Play; Prevalence; Rate; Research; Research Personnel; Resistance; Resources; Risk; Risk Factors; Role; Sequence Homology; Somatomedins; Specimen; Staging; Standards of Weights and Measures; Stem Cell Development; Testing; Time; Time Study; Vascular Diseases; Virus; Visit; Woman; base; cohort; design; disorder risk; human data; insulin secretion; interest; mortality; peptide hormone; prevent; prospective; response; tumor

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.

这项流行病学研究将检查胰岛素样生长因子（IGF）轴对 艾滋病毒和人乳头瘤病毒（HPV），两种性传播病毒的发病机制。最近的数据表明 IGF轴通过影响细胞增殖和存活在宿主免疫中发挥作用， 推测它也可能影响艾滋病毒疾病进展的速度。IGF-I，一种促有丝分裂/抗凋亡激素 在动物模型中，活性可以增加淋巴细胞计数，甚至诱导胸腺再生。 FIV感染的猫与此相反，主要的IGF结合蛋白（IGFBP）IGFBP-3具有间接（螯合） IGF-I）和直接（IGF-I非依赖性）抗有丝分裂/促凋亡活性，并假设加速HIV 疾病然而，几乎没有人类数据。我们仅使用基线标本进行了一项试点调查 来自妇女机构间艾滋病毒研究（WIHS），一项正在进行的艾滋病毒阳性（N= 2，793）和艾滋病毒阴性 （N=975）女性，1994年开始。101例艾滋病临床病例与下列因素有关？IGFBP- 3（HR=2.7;1.3-5.4），在广泛使用HAART（前HAART）之前获得的数据/标本中[重印1] - 与IGFBP-3提出的对免疫系统的抗有丝分裂/促凋亡作用一致。协会 IGF-I与艾滋病的关系也在预期的方向上，尽管不显著（HR=0.64;0.35-1.18）， ? IGFBP-3（Ptrend=0.02）和？IGF-I（Ptrend=0.02）与CD 4 + T细胞快速下降相关。的作用 在137名HIV阴性妇女中研究了HPV自然史中的IGF轴。致癌HPV的持续存在是 相关的？IGF-I/IGFBP-3比值（HR=7.1;1.8-25），而？IGFBP-3与非常低的风险相关， 致癌HPV阳性宫颈瘤变（HR= 0.07; 0.01-0.66）;大多数其他结果无显著性，但 预期的方向-与IGF轴对其他肿瘤的影响和最近的横截面一致 宫颈肿瘤的研究。这些前瞻性试验数据具有明确的临床意义。对于艾滋病毒，他们意味着 IGF轴可能被用作治疗的靶点，以减缓HIV疾病（延长时间，直到 需要使用HAART）。如果在目前的研究中，我们在使用HAART的女性中发现类似的结果， 建议在HAART期间也针对IGF轴。同样，对于HPV，我们的数据表明IGF轴可能 在治疗/预防疾病方面具有尚未开发的潜力。因此，该项目值得注意的是， 流行病学和临床研究的几个新领域。在这项资助下，我们将首次研究 使用HAART的女性;在连续的研究访视中重复检测IGF-I和IGFBP-3， 表征IGF-I和IGFBP-3暴露;研究其他IGF轴相关成分，包括IGF-II，游离 （生物活性）IGF-I和C肽。这笔赠款还将大大增加每个终点的病例数量。 具体目的是研究IGF-轴在以下方面的作用：（1）未使用抗HIV药物的女性的HIV疾病进展 HAART（基于HAART时代之前获得的样本/数据）;（2） 使用HAART的妇女;（3）HIV阳性和阴性妇女中致癌HPV的自然史。