ORAL VACCINE INDUCED CELLULAR IMMUNITY AGAINST HIV1

过去十年积累的证据加强了这一论点 T细胞介导的抗HIV保护机制，包括 细胞毒性T淋巴细胞（CTL）和分泌趋化因子的T细胞。 一 这是开发HIV-1疫苗的主要障碍， 然而，这种免疫性缺乏T细胞介导的反应， 这与保护有关。 例如，没有明确的 CTL应答与抗SIV或HIV保护相关的证据。 另一方面，最近的证据表明，分泌趋化因子的T 细胞可以抑制体外HIV-1感染，这表明了一种新的机制， T细胞介导的保护。 显然，这些研究证明继续 研究T细胞介导的应答可以被 由HIV-1疫苗引起。 在这种情况下，这个中心假设 一种活的口服沙门氏菌-HIV-1疫苗载体将诱导 这种反应在粘膜和全身隔室。 在初步数据部分，我们提供了免疫学数据， 加强我们的中心假设，并证明重要性， HIV-1抗原放置。 因此，我们表明，单次口服剂量的 沙门氏菌-HIV载体，携带分泌形式的非糖基化gp 120， 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，β趋化因子分泌的CD 4+和 在较小程度上，CD 8 + T细胞在诱导事件期间发育 在口服活沙门氏菌免疫后。 最后，我们证明了 人特异性减毒沙门氏菌菌株CVD 908耐受良好 和免疫原性。 我们现在建议通过进一步探索 HIV抗原在载体内或 宿主和HIV特异性细胞的大小和表型 免疫后粘膜和全身部位的反应 没有沙门氏菌载体 我们认为，这种做法将提供 与口腔发展密切相关的基本信息 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.