INDUCTION OF CELLULAR IMMUNITY AGAINST GAG AND NET BY ORAL VACCINE

过去十年积累的证据加强了T 细胞介导的抗HIV保护机制。的主要障碍 然而，增强这种免疫力的HIV-1疫苗的开发， 缺乏T细胞介导的反应， 保护例如，没有明确的证据表明CTL 预防SIV或HIV的措施。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新机制 体外感染，表明T细胞介导的新机制 保护显然，这些研究证明了继续研究 HIV-1疫苗可诱导T细胞介导的应答。 在这种情况下，这一建议的中心假设是，一个活的口头 沙门氏菌-SIV疫苗载体将在小鼠和非小鼠中诱导这种应答。 人类灵长类动物 在初步数据部分，我们提供了免疫学数据， 强化我们的核心假设因此，我们发现单次口服剂量 沙门氏菌-HIV载体，携带糖基化gp 120的分泌形式， 诱导的gp 120特异性T细胞，其主要由IFN-γ- 分泌CD 4 + T细胞和强烈的gp 120特异性粘膜应答。 此外，我们的数据表明，gp 120特异性β趋化因子分泌 口服免疫后，在粘膜区室中产生应答， 沙门氏菌-HIV疫苗载体。最后，我们证明了人类- 特异性减毒沙门氏菌菌株CVD 908耐受良好， 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 表达嵌合的SIV/MAC/239 Gag-Nef融合体，并表征 这些构建体对SIV特异性T细胞应答免疫原性 小鼠此外，沙门氏菌-SIV构建体， 小鼠中的SIV特异性T细胞应答将在免疫组织化学中进行评估。 免疫原性和攻击试验。我们认为 这种方法将提供与 开发口服沙门氏菌-HIV-1疫苗。

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.