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

描述(申请人提供)：许多基于T细胞的人类免疫缺陷病毒(HIV)疫苗正在进行临床试验。2007年，一项有希望的研究在没有显示出保护作用的证据后被取消，这突显出人们对针对艾滋病毒的保护性T细胞反应的性质知之甚少。我们发现，感染了猴免疫缺陷病毒(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是一种与艾滋病毒在人类中引起相同疾病的病毒。MCM的显著特征是其非常简单的遗传学。这使研究人员能够识别将对SIV产生可预测的T细胞反应的动物群体，并利用这些动物来促进我们对艾滋病毒和SIV的T细胞免疫的了解。 我们假设，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诱导出广泛的T细胞特异性。很难在人类身上测试这一假说，所以我们将利用SIV MCM的简单遗传学来测试这一假说。这些实验依赖于主要组织相容性复合体(MHC)I类基因的纯合子或杂合子的MCM组，MHC I类基因将SIV衍生的多肽呈递给T细胞。我们预测，当SIV致病毒株攻击时，MHC杂合子MCM向T细胞递送的多肽是MHC纯合子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，与MHC杂合的MCM相比，MHC纯合的动物识别的SIV CD8 T细胞肽更少，这将导致纯合子动物的病毒负担更高。接下来，我们将生产一种SIV菌株，其中在SIV感染过程中通常被识别的T细胞表位被“敲除”，并询问这种病毒能否被MCM的免疫系统有效地控制。最后，我们将用一种弱化的SIV疫苗株来免疫MCM，这种疫苗株能引起强大的免疫反应。MCM将受到不含特定T细胞表位的SIV“敲除”毒株的挑战。由于疫苗和挑战病毒将主要在确定的T细胞表位上有所不同，本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。综上所述，这些实验将从根本上促进我们对T细胞宽度在控制HIV和SIV中的重要性的理解，并有助于确定是否应将激发广泛的CD8 T细胞“谱系”作为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袭。在这项工作中，我们将使用一种独特的动物模型来确定针对艾滋病病毒内多个靶点进行不同细胞免疫反应的能力是否会影响感染个体控制病毒复制的能力。

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.