Suppressors of cytokine signaling (SOCS) in HAART-treated HIV infection

描述（由申请人提供）：尽管抗病毒治疗取得了进展，但并非所有患者都能完全控制人类免疫缺陷病毒（HIV）感染。大多数接受HAART治疗的感染艾滋病毒的妇女在治疗后表现出良好的病毒控制和CD4计数的恢复。然而，通过对HIV和其他常见微生物的记忆反应中细胞因子的分泌来评估，大约三分之一的病毒反应和CD4计数良好的患者CD4 T细胞功能恢复较差。这种功能差异的原因尚不清楚，但很有必要进行研究，因为那些细胞因子分泌不良的患者，反映了CD4 T细胞功能的缺陷，尽管HAART治疗，疾病进展的风险可能会增加。此外，如果治疗失败或中断，疾病的严重程度可能会加速。这一观察结果也强调了这样一个事实，即在接受治疗的HIV感染中，CD4计数的恢复并不总是与CD4功能的恢复相关。目前的DNA测序技术已经允许绘制人类基因组中的单核苷酸多态性（SNPs），这为研究影响人类疾病发病机制的遗传因素提供了可能性。通过研究遗传因素和免疫功能的双重方法，我们目前正在研究细胞因子分泌（干扰素- γ和白细胞介素-10）及其与相应细胞因子基因核苷酸多态性的关系，使用妇女机构间艾滋病毒研究（WIHS）中特征明确的妇女队列。细胞因子信号抑制蛋白（SOCS蛋白）是一种对细胞因子分泌具有有效调节作用的新蛋白家族，我们建议研究其在hiv感染妇女T辅助细胞功能中的作用。我们的目的是研究SOCS1、SOCS2和SOCS3的mRNA表达水平，以及相应SOCS基因的核苷酸多态性。新出现的结果将提供证据，证明SOCS1、SOCS2和SOCS3基因中的snp是否与分泌细胞因子水平相关（数据来自我们目前的研究），以及它们在HIV感染治疗后免疫恢复和疾病进展中的作用。这种新方法将结合分子流行病学和细胞免疫学的专业知识，并将推进我们目前对HIV感染和治疗效果的理解。我们还期望更好地了解控制HIV感染中的免疫功能可能导致改进的治疗方法。所提议的研究的成功很大程度上得益于从参与妇女保健的妇女那里获得的大量数据和储存库样本。该结果将作为对WIHS妇女细胞因子功能和遗传多态性进行更大更全面研究的初步数据。公共卫生相关性：尽管HAART在控制艾滋病毒感染中的病毒载量方面是有效的，但在妇女机构间艾滋病毒研究（WIHS）中，约有三分之一的接受治疗的妇女表现出记忆性CD4 T细胞分泌抗病毒因子干扰素γ的能力较低，这表明CD4计数相对恢复，但功能恢复较差。此外，在HIV感染中也经常观察到细胞炎症标志物。我们在此建议研究控制干扰素分泌的蛋白质编码基因在这些妇女CD4功能恢复不良的原因中的作用。我们还将研究这些基因在细胞炎症水平上的作用。随着感染艾滋病毒的妇女人数的增加，特别是在非洲裔美国人和拉丁裔少数民族中，了解尽管进行了有效的抗病毒治疗，但疾病进展的原因是高度相关的。

DESCRIPTION (provided by applicant): Despite advances in antiviral therapy, control of infection with the human immunodeficiency virus (HIV) is not completely achieved in all patients. A majority of HIV-infected women receiving HAART present good virus control and recovery of CD4 counts upon treatment. However, about a third of those with good viral response and CD4 counts have a poor recovery of CD4 T cell function as evaluated by secretion of cytokines in memory responses to HIV and other common microorganisms. The reasons for this discrepancy in function are unclear but important to investigate because those patients with poor cytokine secretion, reflecting a defective CD4 T cell function, may be at increased risk of disease progression despite HAART. In addition, disease severity may accelerate in case of therapy failure or interruption. This observation also highlights the fact that recovery of CD4 counts in treated HIV infection does not always correlate with recovery of CD4 function. Current technology for DNA sequencing has allowed for mapping of single nucleotide polymorphisms (SNPs) in the human genome, which opens the possibility to investigate genetic factors influencing the pathogenesis of disease in humans. Applying a dual approach by investigating genetics factors and immune function, we are currently studying cytokine secretion (interferon-gamma and interleukin-10) and its association with nucleotide polymorphisms in the corresponding cytokine genes using the well-characterized cohort of women in the Women's Interagency HIV Study (WIHS). We propose to investigate the role that the suppressors of cytokine signaling (SOCS proteins), a novel protein family with potent modulatory effect on cytokine secretion, may have on T helper cell function in HIV-infected women. We aim to investigate levels of mRNA expression for SOCS1, SOCS2 and SOCS3, as well as nucleotide polymorphisms in the corresponding SOCS genes. The emerging results will provide evidence on whether SNPs in any of the SOCS1, SOCS2 and SOCS3 genes are associated with levels of secreted cytokines (data available from our current studies) and their role in immune recovery and disease progression following treatment of HIV infection. This novel approach will combine the expertise of molecular epidemiology with cellular immunology and will advance our current understanding of HIV infection and effect of treatment. We also expect that a better understanding of immune function in controlled HIV infection may lead to improved therapies. The success of the proposed study is greatly facilitated by the availability of extensive data and repository samples from the participating women in WIHS. The results will be used as preliminary data for a larger and more comprehensive study of cytokine function and genetic polymorphisms in WIHS women. PUBLIC HEALTH RELEVANCE: Although HAART is efficient in controlling viral load in HIV infection, about a third of treated women in the Women's Interagency HIV Study (WIHS) present low capacity for secretion of the antiviral factor interferon-gamma by memory CD4 T cells, indicating relative recovery of CD4 counts but poor recovery of function. Also, markers of cell inflammation are commonly observed in HIV infection. We propose here to study the role of genes coding for proteins that control interferon-gamma secretion as a reason for poor recovery of CD4 function in these women. We will also study the role of these genes on the level of cell inflammation. As the number of HIV-infected women increase, especially among African-American and Latino minorities, it is highly relevant to understand the reasons for disease progression despite efficient anti-viral treatment.