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

描述(由申请人提供)：本申请是国家过敏和传染病研究所授予医师-科学家实习生的博士前奖学金。申请者是宾夕法尼亚大学佩雷尔曼医学院的医学科学家培训项目实习生，该奖项将帮助他实现成为传染病领域的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已经活跃了艾滋病疫苗研究领域，即使在令人失望的临床试验结果之后。在F30的这一应用中，发现了一种针对HIV-1 5‘前导RNA序列编码的多肽的新免疫应答。这些发现令人惊讶，因为HIV-15的5‘端包含许多调控元件，编码在其RNA二级结构中，一直被认为是翻译沉默的。初步数据显示恰恰相反，5‘端编码免疫原肽，驱动强大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遏制中发挥作用，因为保守RNA结构中的病毒逃逸突变预计会对病毒复制适合性造成重大损失。目前的提案将检验这一假设。在目标I中，申请人提出了对20例HIV-1感染者的5‘前导肽(5LP)表达和抗5LP靶向细胞免疫反应的系统分析。在目标2中，申请人建议通过研究病毒突变逃避抗5LP反应所导致的病毒适合性成本以及5LP在不同HIV-1亚型内和不同亚型之间的抗原交叉反应来研究5LP作为潜在的疫苗免疫原。导致本建议的大部分前期工作是在少数感染HIV-1的人类受试者和SIVmac239只感染SIVmac239只印度猕猴身上进行的。这项应用代表了在大量人类受试者中对5LP靶向免疫反应的第一次系统分析，这将允许就这些反应在病毒-宿主免疫发病机制中的作用以及在疫苗开发中的潜在作用得出一般性结论。

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.