INDUCTION OF CELLULAR IMMUNITY AGAINST GAG AND NET BY ORAL VACCINE

过去十年积累的证据加强了T 针对艾滋病毒的细胞介导的保护机制。一个主要的障碍 然而，能够产生这种免疫力的HIV-1疫苗的开发， 缺乏T细胞介导的反应，这种反应与 保护。例如，没有确凿的证据表明CTL与 预防SIV或HIV的应对措施。另一方面，最近 有证据表明，分泌趋化因子的T细胞可以抑制HIV-1 体外感染提示T细胞抑制HIV-1的新机制 体外感染，提示了T细胞介导的一种新机制 保护。显然，这些研究证明了继续调查 HIV-1疫苗可以诱导T细胞介导的反应的方法。 在这一点上，这项提议的中心假设是，一次现场口头 沙门氏菌-SIV疫苗载体将在小鼠和非 人类灵长类动物。 在初步数据部分，我们提供了免疫学数据， 强化我们的中心假设。因此，我们证明了单次口服剂量 沙门氏菌-HIV载体，携带分泌形式的糖基化gp120， 诱导以干扰素-γ为主的gp120特异性T细胞。 分泌CD4T细胞和强烈的gp120特异性粘膜反应。 此外，我们的数据表明，gp120特异性的β趋化因子分泌 口服免疫后粘膜小室出现免疫应答 一种沙门氏菌HIV疫苗载体。最后，我们展示了人类-- 特异性减毒沙门氏菌菌株CVD 908耐受性良好， 志愿者体内的免疫原性。 我们现在建议通过构建沙门氏菌载体来扩展这些发现 表达嵌合SIV/MAC/239 Gag-Nef融合蛋白，并鉴定 构建的SIV特异性T细胞应答的免疫原性 老鼠。此外，沙门氏菌-SIV结构引起了最强烈的 将在小鼠中评估SIV特异性T细胞反应 非人灵长类动物的免疫原性和挑战试验。我们相信 这种方法将提供与 口服沙门氏菌-HIV-1疫苗的研制。

Evidence accumulated over the past decade has strengthened the case for T cell-mediated mechanisms of protection against HIV. A major impediment to the development of an HIV-1 vaccine that elicits such immunity, however, has been the lack of a T cell-mediate response that correlates with protection. For example, there is no definitive evidence correlating CTL responses with protection against SIV or HIV. On the other hand, recent evidence showing that chemokine-secreting T cells can suppress HIV-1 infection in vitro suggest a new mechanism of T cells can suppress HIV-1 infection in vitro, suggests a new mechanism of T cell-mediated protection. Clearly, these studies justify continued investigation of the means by which T cell-mediated responses can be induced by HIV-1 vaccines. In this vein, the central hypothesis of this proposal is that a live oral Salmonella-SIV vaccine vector will induce such responses in mice and non human primates. In the preliminary data section we present immunological data that strengthen our central hypothesis. Thus, we showed that a single oral dose of a Salmonella-HIV vector, bearing a secreted form of glycosylated gp120, induced gp120-specific T cells that were predominated by IFN-gamma- secreting CD4+ T cells and a strong gp120-specific mucosal response. Furthermore, our data suggest that gp120-specific beta chemokine-secreting responses develop in the mucosal compartment after oral immunization with a Salmonella-HIV vaccine vector. Finally, we have shown that human- specific attenuated Salmonella strain CVD 908 is well tolerated and immunogenic in volunteers. We now propose to extent these finding by constructing Salmonella vectors that express chimeric SIV/MAC/239 Gag-Nef fusions and to characterize the immunogenicity of these constructs for SIV-specific T cell responses in mice. Further, the Salmonella-SIV construct that elicits the strongest SIV-specific T cell responses in mice will be evaluated in an immunogenicity and challenge trial in non-human primates. We believe that this approach will provide fundamental information germane to the development of an oral Salmonella-HIV-1 vaccine.