DENDRITIC CELLS AS ADJUVANTS FOR RESISTANCE TO HIV-1

成功的HIV-1疫苗可能必须诱导强大的CD 4和CD 8 T细胞免疫。例如，有证据表明，在许多免疫实验模型中，病毒特异性CD 8 + T细胞的功能需要CD 4 + T细胞，并且CD 8 + T细胞提供对SIV和HIV-1的抗性。同样地，EBV相关的淋巴组织增生性疾病在AIDS中发展，表明在EBV中也需要CD 4 + T细胞抵抗。树突状细胞（Dendritic cells，DC）是一种特异性的抗原提呈细胞，可介导CD 4+和CD 8 + T细胞的联合免疫。因此，我们的假设是，HIV-1和EBV抗原靶向成熟的免疫刺激性DC将导致强的病毒特异性免疫。在这两年的资助中，我们已经学会了用不同的病毒载体将HIV-1和EBV抗原输送到DC，我们发现这些DC然后刺激强烈的T细胞反应。在其他赠款中，我们将携带抗原的DC注射给健康志愿者，并原位引发快速和广泛的T细胞免疫。我们现在将沿着沿着3条线追踪数据：1]为了优化用非干扰性假型HIV-1感染的DC的使用--以在培养物中引发强免疫。然后，该方法将用于检测和量化重要队列中的CD 4和CD 8免疫状态，3例如，暴露的未感染个体、长期非进展者和接受高活性抗逆转录病毒疗法的患者; 2]与沃尔特里德陆军研究所疫苗组合作，用携带重组禽痘的自体DC对志愿者进行疫苗接种。然后将免疫力与直接接种重组禽痘的单独队列进行比较;迄今为止，这种方法尚未诱导强烈或可靠的免疫力。3]利用DC诱导抗EB巴尔病毒的免疫反应，特别是EBNA-1特异性的CD 4 + T细胞。我们已经确定了强烈的CD 4 + T细胞对关键EBNA-1蛋白的反应，现在将使用DC来了解EBNA-1的加工和反应性T细胞的生物学功能。

A successful HIV-1 vaccine will likely have to induce strong CD4 and CD8 T cell immunity. For example, there is evidence that CD4+ T cells are required for the function of virus-specific CD8+ T cells in many experimental models of immunity, and that CD8+ T cells provide resistance against SIV and HIV-1. Likewise, EBV-associated lymphoproliferative disorders develop in AIDS, suggesting a need for CD4+ T cells in resistance in EBV as well. Dendritic cells [DCs) are specialized antigen presenting cells for initial combined CD4+ and CD8+ T cell immunity. Therefore our hypothesis is that the targeting of HIV-1 and EBV antigens to mature, immunostimulatory DCs will lead to strong virus-specific immunity. In the two years of this grant, we have learned to deliver HIV-1 and EBV antigens to DCs with different viral vectors, and we find that these DCs then stimulate strong T cell responses. In other grants, we have injected antigen-bearing DCs to healthy volunteers and elicited rapid and broad T cell immunity in situ. We will now pursue the data along 3 lines: 1] To optimize the use of DCs infected with a non- perturbing, envelope-pseudotyped HIV-1--to elicit strong immunity in culture. This approach will then be used to detect and quantify CD4 and CD8 immune status in important cohorts, 3e.g., exposed uninfected individuals, long term non-progressors, and patients receiving highly active anti-retroviral therapy; 2] To vaccinate, in collaboration with the Walter Reed Army Research Institute vaccine group, volunteers with autologous DCs charged with recombinant avipox. The immunity will then be compared to separate cohorts vaccinated with recombinant avipox directly; an approach that to date has not induced strong or reliable immunity. 3] To use DCs to elicit immunity to Epstein Barr Virus, especially CD4+ T cells specific to EBNA-1. We have identified strong CD4+ T cell responses to the critical EBNA-1 protein and now will use DCs to understand the processing of EBNA-1 and the biological functions of the reactive T cells.