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: 7930666
• 负责人: Thomas C. Friedrich
• 金额: $ 71.67万
• 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/7930666
• 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）：许多针对人类免疫缺陷病毒（HIV）的基于T细胞的疫苗都在临床试验中。一项有前途的研究在2007年没有显示出保护的证据后被取消，强调了对抗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）的毛里求利亚cynomolgus猕猴（MCM），这种病毒是一种与人类艾滋病毒相同的疾病的病毒，为了解保护性T细胞反应提供了前所未有的机会。 MCM的区别特征是它们非常简单的遗传学。这使研究人员能够识别将对SIV进行可预测的T细胞反应的动物组，并使用这些动物来提高我们对T细胞免疫对HIV和SIV的了解。 我们假设到目前为止所测试的HIV疫苗至少由于未能引起广泛的T细胞特异性曲目而至少部分成功。很难在人类中检验这一假设，因此我们将利用其简单的遗传学来检验SIV+ MCM中的这一假设。这些实验依赖于主要组织相容性复合物（MHC）I类基因的MCM组，该基因呈纯合或杂合，将SIV衍生的肽呈现于T细胞。我们预测，当用SIV的致病菌株挑战时，MHC杂合MCM具有与MHC纯合MCM的两倍的能力，因此更有可能用这种AIDS病毒来控制感染。 首先，我们将用致病性SIV和监测SIV疾病进展，公认的T细胞表位数以及病毒进化感染MHC纯合和杂合MCM。我们预计MHC纯合动物将识别出比MHC杂合MCM更少的SIV CD8+ T细胞肽，这将导致纯合动物的病毒负担更高。接下来，我们将产生一种SIV菌株，其中通常在SIV感染期间通常识别的T细胞表位“敲定”，并询问该病毒是否可以通过MCM的免疫系统有效控制。最后，我们将用SIV的疫苗菌株弱化MCM，从而引起有效的免疫反应。 MCM将通过不包含特定T细胞表位的SIV的“基因敲除”菌株挑战。由于疫苗和挑战病毒将主要在定义的T细胞表位中有所不同，因此该实验将确定宽性T细胞反应对衰减SIV提供的令人印象深刻的控制的重要性。综上所述，这些实验将从根本上提高我们对T细胞宽度控制HIV和SIV的重要性的理解，并有助于确定引发广泛的CD8+ T细胞“曲目”是否应该是HIV疫苗的主要目标。研究人员仍然不知道哪种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对艾滋病病毒中多个靶标的多种细胞免疫反应的能力是否影响感染个体控制病毒复制的能力。