Discovery of a Novel Immune Response to the 5' Leader of HIV-1

描述（由申请人提供）：该申请是由美国国家过敏和传染病研究所授予的博士前奖学金，用于内科科学家实习生。申请人是宾夕法尼亚大学佩雷尔曼医学院医学科学家培训计划的实习生，将通过该奖项帮助他实现成为传染病领域内科科学家的职业目标。在HIV和SIV感染的人类和非人类灵长类动物模型中发现的新的免疫反应，即使在令人失望的临床试验结果之后，也为艾滋病疫苗研究领域注入了活力。在这个F30应用中，报告了一种针对hiv - 15 '先导RNA序列编码的肽的新免疫应答的发现。这些发现令人惊讶，因为hiv - 15 '先导蛋白在其RNA二级结构中包含许多编码的调控元件，一直被认为是翻译沉默的。初步数据表明正好相反，5'先导蛋白编码免疫原性肽，驱动有效的细胞免疫反应的发展。申请人假设这些新发现的免疫反应可能在病毒控制中发挥作用，因为保守RNA结构中的病毒逃逸突变预计会对病毒的复制适应性造成重大损失。目前的提案将检验这一假设。在Aim I中，申请人提议对20名HIV-1感染者的5′前导肽（5LP）表达和抗5LP靶向细胞免疫反应进行系统分析。在Aim 2中，申请人提出通过研究抗5lp反应中病毒突变逃逸导致的病毒适应度成本以及不同HIV-1亚型内部和之间5lp的抗原交叉反应性来研究5lp作为潜在疫苗免疫原的可能性。导致本建议的大部分初步工作是在少数感染艾滋病毒-1的人类受试者和感染SIVmac239的印度恒河猴中进行的。该应用代表了对大量人类受试者的5LP靶向免疫反应的首次系统分析，将允许得出关于这些反应在病毒-宿主免疫发病机制和潜在疫苗开发中的作用的一般结论。

DESCRIPTION (provided by applicant): This application is for a predoctoral fellowship awarded by the National Institute of Allergy and Infectious Diseases to physician-scientist trainees. The applicant is a Medical Scientist Training Program trainee at the Perelman School of Medicine at the University of Pennsylvania and would be assisted by this award in achieving his career goals of becoming a physician-scientist in the field of Infectious Diseases. Novel immune responses identified in human and nonhuman primate models of HIV and SIV infection have invigorated the field of AIDS vaccine research, even in the wake of disappointing clinical trial outcomes. Reported in this F30 application is the discovery of a novel immune response against peptides encoded by the HIV-1 5' leader RNA sequence. These findings come as a surprise because the HIV-1 5' leader, which contains numerous regulatory elements encoded in its RNA secondary structure, has been thought to be translationally silent. Preliminary data suggest just the opposite, that the 5' leader encodes immunogenic peptides that drive the development of potent cellular immune responses. The applicant postulates that these newly discovered immune responses may play a role in virus containment because viral escape mutations in conserved RNA structures would be expected to impose significant costs to viral replicative fitness. The current proposal will test this hypothesis. In Aim I, the applicant proposs a systematic analysis of 5' leader peptide (5LP) expression and anti-5LP targeted cellular immune responses in 20 HIV-1 infected humans. In Aim 2, the applicant proposes to investigate 5LPs as potential vaccine immunogens by studying viral fitness costs resulting from viral mutational escape from anti-5LP responses and the antigenic cross-reactivity of 5LPs within and among different HIV-1 subtypes. Most of the preliminary work leading to the present proposal has been conducted in a small number of HIV-1 infected human subjects and in SIVmac239 infected Indian rhesus macaques. This application represents the first systematic analysis of 5LP targeted immune responses in a robust number of human subjects that will allow for general conclusions to be reached regarding role of these responses in virus-host immunopathogenesis and potentially in vaccine development.