T cell immunity to HIV using recombinant enteroviruses

描述(由申请人提供)：一种成功的HIV疫苗可能必须引起保护性的T辅助细胞、T细胞毒性和B细胞反应。目前的提案重点是使用活的重组肠道病毒对艾滋病毒的T细胞免疫。我们已经确定了一种肠道病毒，一种柯萨奇病毒，它是高度减毒但具有免疫原性的。该申请涉及柯萨奇病毒作为艾滋病毒疫苗载体的开发，是一项概念验证提案。这项研究的一个目标是构建柯萨奇/HIV重组体，它将引发HIV特异性的T辅助细胞和T细胞毒反应。将使用两种策略来构建能够诱导两种类型的T细胞反应的重组体。为了激发T辅助细胞反应，HIV多肽将在柯萨奇病毒的衣壳蛋白中表达。为了产生T细胞毒性细胞反应，HIV序列将在感染细胞中表达，但不会被整合到后代病毒粒子中。这项研究的另一个目的是评估柯萨奇/HIV重组体在小鼠中的免疫原性。重组子能诱导HIV特异性T辅助细胞和T细胞毒细胞反应吗？这项研究的最终目标是确定能够增强免疫反应的参数。感染途径是否影响T辅助细胞和T细胞毒反应的大小？细胞因子佐剂能增强T细胞免疫功能吗？这项工作的结果将为开发合适的重组体在以后的研究中在非人类灵长类动物模型中进行测试提供框架。能够诱导T细胞对HIV免疫的重组体可能是作为预防性HIV疫苗的免疫原合成的一部分。

DESCRIPTION (provided by applicant): A successful HIV vaccine will likely have to elicit protective T helper, T cytotoxic, and B cell responses. The current proposal focuses on T cell immunity to HIV using a live, recombinant enterovirus. We have identified an enterovirus, a coxsackievirus, that is highly attenuated yet immunogenic. The application addresses the development of coxsackievirus as a vaccine vector for HIV and is a proof-of-concept proposal. One goal of the study is the construction of coxsackie/HIV recombinants which will elicit HIV-specific T helper and T cytotoxic responses. Two strategies will be used to construct recombinants capable of inducing both types of T cell response. To elicit T helper cell responses, HIV peptides will be expressed within a capsid protein of coxsackievirus. To generate T cytotoxic cell responses, HIV sequences will be expressed in infected cells but will not be incorporated into progeny virions. Another goal of the study is to evaluate the immunogenicity of the coxsackie/HIV recombinants in mice. Can the recombinants induce HIV-specific T helper and T cytotoxic cell responses? The final goal of the study is to identify parameters that are able to augment the immune responses. Does the route of infection influence the magnitude of the T helper and T cytotoxic cell responses? Can T cell immunity be augmented with cytokine adjuvants? The results obtained from this work will provide the framework for developing appropriate recombinants for testing in a non-human primate model in a later study. Recombinants that can elicit T cell immunity against HIV could be part of a "cocktail" of immunogens used as a preventive HIV vaccine.