DENDRITIC CELLS AS ADJUVANTS FOR RESISTANCE TO HIV-1

一种成功的HIV-1疫苗很可能必须诱导强大的CD4和CD8T细胞免疫。例如，有证据表明，在许多免疫实验模型中，CD4+T细胞是病毒特异性CD8+T细胞发挥功能所必需的，CD8+T细胞对SIV和HIV-1具有抵抗力。同样，EB病毒相关的淋巴增殖性疾病在艾滋病中发展，这表明在EBV中也需要CD4+T细胞来抵抗。树突状细胞(DCs)是一种特异性的抗原提呈细胞，用于初始结合的CD4+和CD8+T细胞免疫。因此，我们的假设是，将HIV-1和EBV抗原靶向成熟的、免疫刺激的DC将导致强大的病毒特异性免疫。在这笔赠款的两年里，我们已经学会了用不同的病毒载体将HIV-1和EBV抗原传递给DC，我们发现这些DC随后会激发强烈的T细胞反应。在其他赠款中，我们向健康志愿者注射携带抗原的树突状细胞，并在原位诱导快速和广泛的T细胞免疫。我们现在将沿着3条路线追踪数据：1]优化使用感染了无扰动的、包膜假型HIV-1的DC，以在培养中诱导强大的免疫力。然后，这种方法将被用来检测和量化重要队列中的CD4和CD8免疫状态，例如，暴露于病毒中的未感染者、长期无进展者和接受高效抗逆转录病毒治疗的患者；2]与沃尔特里德陆军研究所疫苗小组合作，为自体DC感染重组禽流感的志愿者接种疫苗。然后将这种免疫与直接接种重组禽痘的单独队列进行比较；这种方法到目前为止还没有诱导出强大或可靠的免疫。[目的]利用树突状细胞(DC)诱导抗EB病毒免疫，尤其是EBNA-1特异性的CD4+T细胞。我们已经确定了CD4+T细胞对关键的EBNA-1蛋白的强烈反应，现在将使用DC来了解EBNA-1的处理过程和反应性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.