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

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细胞的疫苗正在进行临床试验。2007年，一项有希望的研究在没有证据显示保护作用后被取消，这凸显了人们对T细胞对艾滋病毒的保护性反应的性质知之甚少。我们已经发现，感染猿猴免疫缺陷病毒（SIV）的猕猴（MCM）为理解保护性T细胞反应提供了前所未有的机会。MCM的显着特点是它们非常简单的遗传学。这使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，并利用这些动物来加深我们对HIV和SIV T细胞免疫的理解。 我们推测，到目前为止测试的HIV疫苗没有成功，至少部分原因是它们未能引起广泛的T细胞特异性。很难在人类中验证这一假设，因此我们将利用SIV+ MCM的简单遗传学来验证这一假设。这些实验依赖于MCM组，其对于将SIV衍生肽呈递给T细胞的主要组织相容性复合体（MHC）I类基因是纯合或杂合的。我们预测，MHC杂合MCM有能力提出两倍多的肽T细胞的MHC纯合MCM时，与SIV的致病株的挑战，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纯合和杂合MCM，并监测SIV疾病进展、识别的T细胞表位的数量和病毒进化。我们预计，MHC纯合动物将识别较少的SIV CD8+ T细胞肽比MHC杂合MCM，这将导致更高的病毒负荷的纯合动物。接下来，我们将生产一种SIV菌株，其中在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，我们将用SIV的弱疫苗株免疫MCM，以激发有效的免疫应答。将用不含特异性T细胞表位的SIV的“敲除”毒株攻击MCM。由于疫苗和攻击病毒主要在确定的T细胞表位内不同，因此该实验将确定广泛定向的T细胞应答对减毒SIV提供的令人印象深刻的控制有多重要。总之，这些实验将从根本上推进我们对T细胞宽度在控制HIV和SIV中的重要性的理解，并有助于确定是否引发广泛的CD8+ T细胞“库”应该是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，我们将使用一个独特的动物模型，以确定是否有能力安装不同的细胞免疫反应对艾滋病病毒内的多个目标影响感染个体的能力，以控制病毒复制。

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.