ANERGY, APOPTOSIS AND CD28 IN CD8+ T CELLS DURING AIDS

艾滋病期间 CD8 T 细胞的无能、凋亡和 CD28

• 批准号: 2073118
• 负责人: DOROTHY E. LEWIS
• 金额: $ 21.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2073118
• 关键词: AIDS; CD28 molecule; anergy; apoptosis; cytotoxic T lymphocyte; genetic regulation; human subject; immunoprecipitation; in situ hybridization; leukocyte activation /transformation; longitudinal human study; molecular pathology; tissue /cell culture; transcription factor; western blottings

CD8+ T cells in human immunodeficiency virus (HIV)-infected people undergo significant alterations in phenotype and function during the disease. There is chronic activation as indicated by an increase in the expression of activation antigens such as CD38, DR, and CD57. The development of preactivated major histocompatibility complex (MHC)-restricted, HIV- specific cytotoxic T lymphocyte also is a unique feature of infection. The CD8+ T cells also are anergic and apoptotic in vitro and have reduced cloning efficiency. Late in infection, HIV-specific CTL function is lost which may be responsible for HIV disease progression. Our hypothesis is that many of these observations are related directly to the loss of surface expression of the important T cell activation molecule, CD28. The interaction of CD28 with ligands on antigen-presenting cells is known to be crucial for T cell activation. We propose to address the importance of CD28 function in HIV infection by three specific aims. Specific Aim 1 is to perform a cross-sectional study of HIV+ people early after infection, during the asymptomatic period, in patients with AIDS, and in long-term survivors. We will determine the timing of CD28 loss on CD8+ T cells as a function of disease status, immune function, virologic status, and susceptibility of cells to apoptosis. These studies will determine the clinical significance of our observation and will ask whether the CD8 cells are affected early in infection or whether intact CD28 expression in a determinant of long-term survival. Specific Aim 2 is to perform a longitudinal study to address whether the loss of HIV-specific CTL function late in infection is due to loss of CD28 expression, associated with viremia, development of anergy, apoptosis, and clinical progression. This study addresses whether loss of containment of HIV by cytotoxic T cells is due to loss of CD28 expression. Specific Aim 3 examines a specific mechanism of CD28 gene regulation. A major hypothesis of HIV pathogenesis is that a T-1 to T-2 switch occurs in cytokine production as the disease progresses. No one has addressed the ramifications of the hypothesis on development of CD8+ T cells or their function. Preliminary data indicate that a T-2 cytokine environment causes CD28 down-regulation on CD8+ T cells from control individuals. We propose to test the hypothesis that CD28 gene transcription is negatively regulated by T-2 cytokines via a reduction in NF-kB activity. Thus, these studies will explore the molecular regulation of CD28 expression. This proposal has significance for vaccine design and gene therapy approaches because understanding the role of CD28 in containment of HIV by CD8+ T cells may lead to augmentation or intervention.

人类免疫缺陷病毒(HIV)感染者CD8+T细胞 疾病过程中表型和功能的显著改变。 有慢性激活，如表达增加所示 激活抗原，如CD38、DR和CD57。的发展。 预活化的主要组织相容性复合体(MHC)限制性的，HIV- 特异性细胞毒性T淋巴细胞也是感染的一个独特特征。 CD8+T细胞在体外也是无能和凋亡的，并且已经减少 克隆效率。感染晚期，HIV特异性CTL功能丧失 这可能是导致HIV疾病发展的原因。我们的假设是 这些观察结果中的许多都直接与 重要T细胞活化分子CD28的表面表达。这个 已知CD28与抗原提呈细胞上的配体相互作用 对T细胞的激活至关重要。我们建议解决以下问题的重要性 CD28在HIV感染中的作用有三个特异性目的。具体目标1是 为了在感染后早期对HIV+人群进行横断面研究， 在无症状期，在艾滋病患者中，在长期 幸存者。我们将确定CD8+T细胞CD28丢失的时间作为 疾病状态、免疫功能、病毒学状态和 细胞对凋亡的敏感性。这些研究将确定 我们观察的临床意义并将询问CD8是否 细胞在感染早期受到影响，或者完整的CD28表达是否在 是长期生存的决定因素。具体目标2是执行一项 一项纵向研究，以解决艾滋病毒特异性CTL是否丢失 感染晚期的功能是由于CD28表达的丧失，相关 伴随病毒血症，发展为无能、细胞凋亡和临床进展。 这项研究解决了细胞毒性T细胞是否会失去对HIV的遏制 细胞是由于CD28表达缺失所致。《特定目标3》考查一个 CD28基因调控的具体机制。艾滋病毒的一个主要假说 发病机制是T-1到T-2的转换发生在细胞因子的产生中， 疾病会继续发展。还没有人谈到这一事件的后果 CD8+T细胞发育或功能假说。初步 数据表明，T-2细胞因子环境导致CD28下调 在对照组CD8+T细胞上的表达。我们建议测试一下 CD28基因转录受T-2负调控的假说 通过降低核因子-kB活性而产生的细胞因子。因此，这些研究将 探讨CD28表达的分子调控。这项建议具有 疫苗设计和基因治疗方法的重要性，因为 了解CD28在CD8+T细胞抑制HIV中的作用可能 导致增加或干预。