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

人类免疫缺陷病毒（HIV）感染者的CD 8 + T细胞 疾病期间表型和功能的显著改变。 存在慢性激活，如表达增加所示。 活化抗原如CD 38、DR和CD 57。 的发展 主要组织相容性复合体（MHC）限制性抗原，HIV- 特异性细胞毒性T淋巴细胞也是感染独特特征。 CD 8 + T细胞在体外也是无反应性和凋亡的，并且具有减少的 克隆效率 感染晚期，HIV特异性CTL功能丧失 这可能是导致HIV疾病进展的原因。 我们的假设是 这些观察结果中有许多与失去 重要的T细胞活化分子CD 28的表面表达。 的 已知CD 28与抗原呈递细胞上配体的相互作用 对T细胞活化至关重要。 我们建议， CD 28在HIV感染中的作用有三个具体目标。 具体目标1是 对感染后早期的HIV阳性人群进行横断面研究， 在无症状期间，在艾滋病患者中， 幸存者 我们将确定CD 8 + T细胞上CD 28丢失的时间， 疾病状态、免疫功能、病毒学状态和 细胞对凋亡的易感性。这些研究将决定 我们的观察的临床意义，并会问是否CD 8 细胞是否在感染早期受到影响，或者是否完整的CD 28表达， 长期生存的决定因素。 具体目标2是执行 纵向研究，以解决是否艾滋病毒特异性CTL的损失 感染后期的功能是由于CD 28表达的丧失， 病毒血症、无反应性发展、细胞凋亡和临床进展。 本研究讨论了细胞毒性T细胞是否会失去对艾滋病毒的遏制作用， 这是由于CD 28表达的缺失。 具体目标3审查了 CD 28基因调控的特殊机制。 艾滋病病毒的一个主要假设 发病机制是T-1到T-2转换发生在细胞因子产生中， 疾病进展。 没有人讨论过 关于CD 8 + T细胞发育或其功能的假说。 初步 数据表明T-2细胞因子环境导致CD 28下调 对来自对照个体的CD 8 + T细胞。 我们建议测试 CD 28基因转录受T-2负调控假说 细胞因子通过减少NF-κ B活性。 这些研究将 探讨CD 28表达的分子调控。 这一建议 疫苗设计和基因治疗方法的意义，因为 了解CD 28在CD 8 + T细胞遏制HIV中的作用， 导致增加或干预。

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.