Defining Immune Deficits in HIV-1 Infected Women

定义 HIV-1 感染女性的免疫缺陷

• 批准号: 7192411
• 负责人: Catherine A Blish
• 金额: $ 11.29万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7192411
• 关键词: AIDS prevention; Acquired Immunodeficiency Syndrome; Address; Agreement; Antibody Formation; Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; Cell division; Cellular Immunity; Chronic; Cryopreserved Cell; Cytolysis; Epidemic; Failure; Flow Cytometry; Future; Goals; HIV; HIV-1; High Risk Woman; Immune; Immune response; Immunity; Individual; Infection; Kenya; Length; Mediating; Methods; Peripheral Blood Mononuclear Cell; Play; Production; Reporting; Research Personnel; Resistance; Role; Sampling; Specificity; Staining method; Stains; T-Cell Proliferation; T-Lymphocyte; Vaccine Design; Vaccines; Variant; Viral; Virus; Woman; cohort; cytokine; insight; neutralizing antibody; pandemic disease; prevent; programs; research study; response; superinfection

DESCRIPTION (provided by applicant): The AIDS pandemic continues unchecked, and the prospect of an effective vaccine provides the best hope for HIV prevention. Our efforts to develop a protective vaccine have been hampered by the fact that we still do not understand correlates of immunity to HIV-1. Ongoing vaccine trials promise to provide insight into whether the immune responses that are involved in controlling HIV-1 replication during chronic infection can also play a role in mediating protection from new infection with HIV-1. Recent reports of HIV-1 superinfection (also called re-infection, defined as infection by a second virus after the first virus is already established in the individual), suggest that the immune responses generated during natural infection do not necessarily induce protective immunity. Thus, identifying potential immune deficits in superinfected individuals will be important for vaccine design. Our lab has recently identified several cases of HIV-1 superinfection among a cohort of high-risk women in Mombasa, Kenya. We hypothesize that deficits in both humoral and cellular immunity to HIV-1 contribute to the ability of a second viral strain to establish infection. The aims of this proposal are to characterize the humoral and cellular immune responses to HIV-1 in superinfected individuals, and to compare these responses to those of women who have not become superinfected. To analyze the humoral immune responses, we will first generate a panel of full length, functional envelope clones from initially infecting and superinfecting strains. We will use these envelopes to develop a panel of viruses with which we can assess the potency and the breadth of the neutralizing antibody responses in superinfected women and in women who do not show evidence of superinfection. We aim to identify correlates of cellular immunity using multiparameter flow cytometry and multiplex cytokine assessment following stimulation of peripheral blood mononuclear cells with HIV-1 and non-HIV-1 antigens. We will assess whether there are deficits or changes in cytokine production, cytolysis, and proliferative capacity among CD4+ and CD8+ T cells in superinfected women. Analyses of the humoral and cellular immune responses of women who have become superinfected will aid in defining correlates of both protective and failed immunity to HIV; such advances will provide key insights to incorporate into future vaccine design.

描述（由申请人提供）：艾滋病的流行仍在继续，不受控制，有效疫苗的前景为预防艾滋病毒提供了最大的希望。由于我们仍然不了解 HIV-1 免疫的相关性，我们开发保护性疫苗的努力受到了阻碍。正在进行的疫苗试验有望深入了解慢性感染期间控制 HIV-1 复制的免疫反应是否也能在介导新的 HIV-1 感染保护中发挥作用。最近关于 HIV-1 重复感染（也称为再感染，定义为第一种病毒在个体中建立后又受到第二种病毒的感染）的报告表明，自然感染过程中产生的免疫反应并不 必然诱发保护性免疫。因此，识别重复感染者潜在的免疫缺陷 个人对于疫苗设计非常重要。我们的实验室最近发现了几例 HIV-1 病例 肯尼亚蒙巴萨一群高危女性中出现重复感染。我们假设赤字 对 HIV-1 的体液免疫和细胞免疫都有助于第二种病毒株建立的能力 感染。该提案的目的是描述重复感染者对 HIV-1 的体液和细胞免疫反应，并将这些反应与未重复感染的女性进行比较。为了分析体液免疫反应，我们将首先从最初感染和重复感染菌株中产生一组全长、功能性包膜克隆。我们将使用这些包膜来开发一组病毒，通过这些病毒我们可以评估重复感染的女性和没有表现出重复感染证据的女性中和抗体反应的效力和广度。我们的目标是在用 HIV-1 和非 HIV-1 抗原刺激外周血单核细胞后，使用多参数流式细胞术和多重细胞因子评估来确定细胞免疫的相关性。我们将评估重复感染女性的 CD4+ 和 CD8+ T 细胞的细胞因子产生、细胞溶解和增殖能力是否存在缺陷或变化。对重复感染的女性的体液和细胞免疫反应进行分析将有助于确定对艾滋病毒的保护性免疫力和失败免疫力的相关性；这些进展将为纳入未来疫苗设计提供重要见解。