CRYPTIC ORFS AS A VACCINE FOR HIV

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：了解完整的病毒特异性反应，最终目标是创造一种能引起CD8+T淋巴细胞(CD8-TL)反应的艾滋病疫苗。 尽管多年来的努力，CD8-TL对艾滋病病毒的全面反应还没有被很好地理解。我们已经获得了令人兴奋的新数据，表明只引起细胞免疫反应的疫苗可以控制异源挑战的急性期病毒复制。我们最近还发现，针对来自env基因另一个读框的隐蔽表位的CD8-TL反应，在限制病毒复制和选择病毒逃逸方面是有效的。我们后来发现，在SIV感染中，隐蔽表位的识别是一种常见的现象。基于这些令人兴奋的数据，我们假设，在疫苗方案中包括cORF将增加激发免疫反应的广度，并将增强感染后的病毒控制。在这里，我们提出了一系列实验，以阐明隐蔽的表位特异性反应在控制艾滋病病毒复制中所起的作用。 在R21阶段，我们将通过扫描感染SIV的猕猴来检查隐藏表位特异性反应的总范围，以寻找跨越SIVmac239基因组中所有隐藏ORF的重叠多肽的反应。 进度： 为R21进行的实验在设计上很简单。我们正在测试SIV感染的猕猴是否针对隐蔽表位产生CD8 T细胞反应，隐蔽表位是由病毒基因组中不应该翻译的部分翻译而来的，或者是来自错误方向的翻译，或者是反义方向。我们已经相当成功地找到了这些。我们已经确定了10多种新的正向翻译产物，其中包含CD8 T细胞表位，最近我们又鉴定了5种反义方向的翻译产物。 出版物： 马内斯，新泽西州，A.D.沃尔什，S.M.皮亚科夫斯基，J.弗洛特，H.L.科勒，A.T.比恩，N.A.威尔逊和D.I.沃特金斯。2010年。CD8+T细胞对隐蔽表位的识别是艾滋病病毒感染的普遍特征。J.Virol 84(21)：11569-74。PMID为20739530。PMCID：PMC2953171。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To understand the complete virus-specific response, with the ultimate goal of creating an AIDS vaccine that elicits CD8+ T lymphocyte (CD8-TL) responses. Despite many years of effort, it is becoming clear that the full extent of the CD8-TL response against AIDS viruses is not well understood. We have obtained exciting new data that indicate that a vaccine that solely elicits cellular immune responses can control acute phase virus replication of a heterologous challenge. We also recently discovered that CD8-TL responses directed against a cryptic epitope, derived from an alternate reading frame of the Env gene, was potent at restricting virus replication and selecting for viral escape. We have since found that recognition of cryptic epitopes is a common occurrence in SIV-infection. Based on these exciting data, we hypothesize that including cORFs in a vaccine regimen will increase the breadth of the elicited immune response and will enhance viral control upon infection. Here, we propose a series of experiments that will shed light on the role cryptic epitope-specific responses play in controlling AIDS virus-replication. In the R21 phase, we will examine the total extent of cryptic epitope-specific responses by scanning SIV-infected macaques for responses to overlapping peptides spanning all cryptic ORFs in the SIVmac239 genome. PROGRESS: The experiments performed for this R21 are simple in design. We are testing whether SIV-infected macaques make CD8 T cell responses against cryptic epitopes, epitopes derived from translation of portions of the viral genome that 'should' not be translated, or from translation in the wrong, or antisense direction. We have been quite successful in finding these. We have identified more than 10 new translation products in the forward direction that contain CD8 T cell epitopes and recently we have identified five translation products in the antisense direction. PUBLICATION: Maness, N.J., A.D. Walsh, S.M. Piaskowski, J. Furlott, H.L. Kolar, A.T. Bean, N.A. Wilson, and D.I. Watkins. 2010. CD8+ T cell recognition of cryptic epitopes is a ubiquitous feature of AIDS virus infection. J. Virol 84(21): 11569-74. PMID 20739530. PMCID: PMC2953171.