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

描述（由申请人提供）：本申请是由过敏和传染病的国家研究所授予的医生，科学家实习生博士前奖学金。申请人是宾夕法尼亚大学佩雷尔曼医学院的医学科学家培训计划实习生，并将获得该奖项的帮助，以实现他成为传染病领域的医生科学家的职业目标。在HIV和SIV感染的人类和非人灵长类动物模型中鉴定的新型免疫应答已经扩展了AIDS疫苗研究领域，即使在令人失望的临床试验结果之后。在该F30申请中报告的是发现了针对由HIV-1 5'前导RNA序列编码的肽的新型免疫应答。这些发现令人惊讶，因为HIV-1的5'前导序列在其RNA二级结构中含有许多编码的调控元件，一直被认为是沉默的。初步数据表明恰恰相反，5'前导序列编码驱动有效细胞免疫应答发展的免疫原性肽。申请人假设，这些新发现的免疫应答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应性造成显著成本。本提案将检验这一假设。在目的I中，申请人提出了在20名HIV-1感染者中对5'前导肽（5LP）表达和抗5LP靶向细胞免疫应答的系统分析。在目的2中，申请人提出通过研究由病毒突变逃避抗5LP应答引起的病毒适应性成本以及不同HIV-1亚型内和之间的5LP抗原交叉反应性，研究5LP作为潜在疫苗免疫原。导致本建议的大部分初步工作已经在少数HIV-1感染的人类受试者和SIVmac 239感染的印度恒河猴中进行。本申请代表了对大量人类受试者中5LP靶向免疫应答的首次系统分析，这将允许就这些应答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.