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

HAART 治疗的 HIV 感染中的细胞因子信号传导 (SOCS) 抑制剂

• 批准号: 8100587
• 负责人: MARIA C VILLACRES
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100587
• 关键词: African American; Antiviral Agents; Antiviral Therapy; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CISH gene; Cell physiology; Cells; Cellular Immunology; Clinical; Code; Cytokine Gene; Cytokine Inducible SH2-Containing Protein; Cytokine Signaling; DNA Sequence; Data; Databases; Disease; Disease Progression; Elements; Failure; Generations; Genes; Genetic; Genetic Polymorphism; HIV; Highly Active Antiretroviral Therapy; Human; Human Genome; Immune; Immune response; Infection; Infection Control; Inflammation; Interferon Type II; Interferons; Interleukin-10; Interruption; Joints; Latino; Lead; Link; Lymphocyte Activation; Mediating; Memory; Messenger RNA; Minority; Molecular Epidemiology; Nucleotides; Opportunistic Infections; Outcome; Participant; Pathogenesis; Patients; Protein Family; Proteins; Recovery; Recovery of Function; Relative (related person); Risk; Role; Sampling; Severity of illness; Signaling Protein; Single Nucleotide Polymorphism; Single Nucleotide Polymorphism Map; T memory cell; Technology; Variant; Viral; Viral Load result; Virus; Virus Diseases; Woman; cohort; cytokine; immune function; improved; mRNA Expression; memory CD4 T lymphocyte; microorganism; novel; novel strategies; public health relevance; response; success; treatment effect

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.

描述(申请人提供)：尽管抗病毒治疗取得了进展，但并不是所有患者都能完全控制人类免疫缺陷病毒(HIV)的感染。大多数接受HAART的艾滋病毒感染妇女表现出良好的病毒控制和治疗后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，那些病毒反应和CD4计数良好的人中，约有三分之一的人CD4T细胞功能恢复较差。这种功能差异的原因尚不清楚，但重要的是要进行调查，因为那些细胞因子分泌不足的患者，反映了CD4T细胞功能缺陷，尽管进行了HAART，但疾病进展的风险可能会增加。此外，在治疗失败或中断的情况下，疾病的严重性可能会加快。这一观察还强调了这样一个事实，即在接受治疗的艾滋病毒感染中，CD4计数的恢复并不总是与CD4功能的恢复相关。目前的DNA测序技术已经能够绘制人类基因组中的单核苷酸多态(SNPs)图，这为研究影响人类疾病发病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，我们目前正在利用妇女机构间艾滋病毒研究(WIHS)中描述良好的女性队列，研究细胞因子分泌(干扰素-γ和白介素10)及其与相应细胞因子基因核苷酸多态的关系。我们建议研究细胞因子信号转导抑制物(SOCS蛋白)家族对HIV感染妇女T辅助细胞功能的影响。SOCS蛋白家族对细胞因子分泌有很强的调节作用。我们的目标是研究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基因中的任何一个的SNPs是否与分泌细胞因子的水平有关(我们目前的研究数据)，以及它们在治疗HIV感染后的免疫恢复和疾病进展中的作用。这一新的方法将结合分子流行病学和细胞免疫学的专业知识，并将促进我们目前对艾滋病毒感染和治疗效果的理解。我们还预计，更好地了解受控艾滋病毒感染的免疫功能可能会带来改进的治疗方法。这项拟议研究的成功很大程度上得益于WIHS中参与妇女的大量数据和资料库样本的可用性。这一结果将被用作对WIHS女性细胞因子功能和遗传多态进行更大和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，约三分之一的接受治疗的妇女表现出记忆CD4T细胞分泌抗病毒因子干扰素-伽马的能力较低，这表明CD4计数相对恢复，但功能恢复较差。此外，细胞炎症的标志物在HIV感染中也很常见。我们建议在这里研究控制干扰素-伽马分泌的蛋白质编码基因的作用，作为这些女性CD4功能恢复较差的原因。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，特别是在非裔美国人和拉丁裔少数群体中，尽管进行了有效的抗病毒治疗，但了解疾病恶化的原因是非常相关的。