ORAL VACCINE INDUCED CELLULAR IMMUNITY AGAINST HIV1

过去十年积累的证据加强了这一论据 关于T细胞介导的预防艾滋病毒的机制，包括 细胞毒性T淋巴细胞(CTL)和分泌趋化因子的T细胞。一个 HIV-1疫苗开发的主要障碍是引起 然而，这种免疫一直缺乏T细胞介导的反应 这与保护相关。例如，没有明确的 CTL反应与预防SIV或HIV相关的证据。 另一方面，最近的证据表明，分泌趋化因子的T细胞 细胞在体外可以抑制HIV-1感染，提示了一种新的机制 T细胞介导的保护。显然，这些研究证明了继续 T细胞介导的反应可通过何种方式被研究 由HIV-1疫苗诱导。在这种情况下，这一点的中心假设 建议是，口服活的沙门氏菌-HIV-1疫苗载体将诱导 这种反应发生在粘膜和系统的隔间。 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，并证明 HIV-1抗原放置。因此，我们发现单剂量口服一次 沙门氏菌-HIV载体，携带分泌形式的非糖基化gp120， 诱导以干扰素-γ为主的gp120特异性T细胞。 分泌CD4+T细胞和强烈的gp120特异性粘膜反应。 此外，我们的数据表明，分泌β趋化因子的CD4+和 在诱导过程中，CD8+T细胞的发育程度较低 口服活沙门氏菌免疫后。最后，我们展示了 人特异性减毒沙门氏菌CVD908菌株耐受性良好 在志愿者中具有免疫原性。 我们现在建议通过进一步探讨 HIV抗原在载体内或载体内放置之间的关系 HIV特异性细胞的宿主、大小和表型 免疫后黏膜和系统部位的反应 没有沙门氏菌的病媒。我们相信，这一方法将提供 基本信息与口语能力的发展密切相关 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, including cytotoxic T lymphocytes (CTLs) and chemokine-secreting T cells. A major impediment to the development of an HIV-1 vaccine that elicits such immunity, however, has been the lack of a T cell-mediated 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 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-HIV-1 vaccine vector will induce such responses in the mucosal and systemic compartments. In the preliminary data section we present immunological data that strengthen our central hypothesis and demonstrate the importance of HIV-1 antigen placement. Thus, we showed that a single oral dose of a Salmonella-HIV vector, bearing a secreted form of non-glcosylated 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 beta chemokine-secreting CD4+ and to a lesser extent CD8+ T cells develop during the inductive events after oral immunization with live Salmonella. Finally, we have shown that human-specific attenuated Salmonella strain CVD908 is well tolerated and immunogenic in volunteers. We now propose to extend these findings by further exploring the relationship between HIV antigen placement within the vector or within the host and the magnitude and phenotype of the HIV-specific cellular responses in mucosal and systemic sites that develop after immunization with out Salmonella vectors. We believe that this approach will provide fundamental information germane to the development of an oral Salmonella-HIV-1 vaccine.