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

描述（由申请人提供）：许多基于T细胞的人类免疫缺陷病毒（HIV）疫苗正在临床试验中。一项很有希望的研究在没有显示出保护作用的证据后，于2007年被取消，这强调了人们对保护性T细胞对艾滋病毒反应的本质知之甚少。我们发现毛里求斯食蟹猴（MCM）感染了猴免疫缺陷病毒（SIV），这种病毒在人类中引起与HIV相同的疾病，为理解保护性T细胞反应提供了前所未有的机会。MCM的显著特征是它们非常简单的基因。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，并利用这些动物来推进我们对HIV和SIV的T细胞免疫的理解。

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.