Defining the importance of CD8+ T Cell Breadth in SIV/HIV protective immunity

定义 CD8 T 细胞宽度在 SIV/HIV 保护性免疫中的重要性

• 批准号: 8117528
• 负责人: Thomas C. Friedrich
• 金额: $ 70.61万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117528
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Attenuated; CD8B1 gene; Clinical Trials; Disease; Disease Progression; Effectiveness; Evaluation; Evolution; Failure; Genetic; Goals; HIV; HIV vaccine; Haplotypes; Homozygote; Human; Immune response; Immune system; Immunity; Individual; Infection Control; Knock-out; MHC Class I Genes; Macaca; Major Histocompatibility Complex; Mediating; Monitor; Nature; Peptides; Rattus; Research Personnel; SIV; Sorting - Cell Movement; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Vaccine Design; Vaccines; Variant; Viral Load result; Virus; Virus Diseases; Virus Replication; Work; base; improved; research study; vaccine evaluation

DESCRIPTION (provided by applicant): Many T cell based vaccines against human immunodeficiency virus (HIV) are in clinical trials. One promising study was canceled in 2007 after showing no evidence of protection, underscoring how little is known about the nature of protective T cell responses against HIV. We have discovered that Mauritian cynomolgus macaques (MCM) infected with simian immunodeficiency virus (SIV), a virus that causes the same disease as HIV causes in humans, offer unprecedented opportunities for understanding protective T cell responses. The distinguishing feature of MCM is their very simple genetics. This allows investigators to identify groups of animals who will mount predictable T cell responses against SIV and use these animals to advance our understanding of T cell immunity to HIV and SIV. We hypothesize that the HIV vaccines tested so far have not been successful at least partially due to their failure to elicit a broad repertoire of T cell specificities. It is difficult to test this hypothesis in humans, so we will test this hypothesis in SIV+ MCM, taking advantage of their simple genetics. These experiments rely on groups of MCM that are either homozygous or heterozygous for major histocompatibility complex (MHC) class I genes that present SIV-derived peptides to T cells. We predict that MHC heterozygous MCM have the capacity to present twice as many peptides to T cells as MHC homozygous MCM when challenged with pathogenic strains of SIV, and therefore are more likely to control infection with this AIDS virus. First, we will infect MHC homozygous and heterozygous MCM with pathogenic SIV and monitor SIV disease progression, the number of recognized T cell epitopes, and virus evolution. We anticipate that MHC homozygous animals will recognize fewer SIV CD8+ T cell peptides than MHC heterozygous MCM, and that this will result in higher viral burdens in the homozygous animals. Next, we will produce a strain of SIV where the T cell epitopes that are normally recognized during SIV infection are "knocked out" and ask whether this virus can be effectively controlled by the immune systems of MCM. Lastly, we will immunize MCM with a weakened vaccine strain of SIV that elicits potent immune responses. The MCM will be challenged with the "knockout" strain of SIV that does not contain specific T cell epitopes. Since the vaccine and challenge viruses will differ primarily within defined T cell epitopes, this experiment will determine how important broadly directed T cell responses are to the impressive control afforded by attenuated SIV. Taken together, these experiments will fundamentally advance our understanding of the importance of T cell breadth in control of HIV and SIV, and help determine whether eliciting a broad CD8+ T cell "repertoire" should be a major goal for HIV vaccines. Researchers still do not know what sorts of immune responses might protect people against AIDS. In this work, we will use a unique animal model to determine whether the ability to mount diverse cellular immune responses against multiple targets within the AIDS virus influences the ability of infected individuals to control virus replication.

描述（由申请人提供）：许多基于 T 细胞的针对人类免疫缺陷病毒 (HIV) 的疫苗正在进行临床试验。 2007 年，一项颇有前景的研究因没有显示出任何保护作用的证据而被取消，这突显出人们对针对 HIV 的保护性 T 细胞反应的性质知之甚少。我们发现，感染了猿猴免疫缺陷病毒 (SIV) 的毛里求斯食蟹猴 (MCM) 为了解保护性 T 细胞反应提供了前所未有的机会。SIV 是一种与人类 HIV 引起的疾病相同的病毒。 MCM 的显着特征是其非常简单的遗传学。这使得研究人员能够识别出能够对 SIV 产生可预测的 T 细胞反应的动物群体，并利用这些动物来加深我们对 HIV 和 SIV 的 T 细胞免疫的理解。 我们假设迄今为止测试的 HIV 疫苗尚未成功，至少部分原因是它们未能引发广泛的 T 细胞特异性。在人类身上检验这一假设很困难，因此我们将利用 SIV+ MCM 简单的遗传学优势，在 SIV+ MCM 中检验这一假设。这些实验依赖于向 T 细胞呈递 SIV 衍生肽的主要组织相容性复合体 (MHC) I 类基因纯合或杂合的 MCM 组。我们预测，当受到 SIV 致病株攻击时，MHC 杂合 MCM 向 T 细胞呈递的肽数量是 MHC 纯合 MCM 的两倍，因此更有可能控制这种艾滋病病毒的感染。 首先，我们将用致病性 SIV 感染 MHC 纯合子和杂合子 MCM，并监测 SIV 疾病进展、识别的 T 细胞表位数量和病毒进化。我们预计 MHC 纯合动物将比 MHC 杂合 MCM 识别更少的 SIV CD8+ T 细胞肽，这将导致纯合动物中更高的病毒负荷。接下来，我们将生产一种SIV毒株，其中SIV感染期间通常识别的T细胞表位被“敲除”，并询问这种病毒是否可以被MCM的免疫系统有效控制。最后，我们将使用 SIV 弱化疫苗株对 MCM 进行免疫，该疫苗株可引发有效的免疫反应。 MCM 将受到不含特定 T 细胞表位的 SIV“敲除”毒株的挑战。由于疫苗和攻击病毒主要在确定的 T 细胞表位内有所不同，因此该实验将确定广泛定向的 T 细胞反应对于减毒 SIV 提供的令人印象深刻的控制有多重要。总而言之，这些实验将从根本上增进我们对 T 细胞广度在控制 HIV 和 SIV 中的重要性的理解，并有助于确定诱导广泛的 CD8+ T 细胞“库”是否应该成为 HIV 疫苗的主要目标。研究人员仍然不知道什么样的免疫反应可以保护人们免受艾滋病的侵害。在这项工作中，我们将使用独特的动物模型来确定针对艾滋病病毒内多个目标发起不同细胞免疫反应的能力是否会影响受感染个体控制病毒复制的能力。