Can vaccine-induced CD8 T cells prevent chronic phase AIDS virus replication?

描述：通过疫苗接种诱导HIV特异性广泛反应性中和抗体是HIV疫苗领域的最终目标。最近有令人鼓舞的报告称，从艾滋病毒感染者身上分离出了中和抗体。然而，现在清楚的是，这些抗体需要相当大的体细胞突变才能进化成有效的中和抗体。因此，通过疫苗接种诱导这些中和抗体仍然是该领域的关键挑战之一。 与中和抗体相比，我们已经 知道如何通过疫苗接种诱导HIV特异性CD 8 T细胞。此外，由这些抗原特异性CD 8 T细胞表达的T细胞受体（TCR）不需要体细胞突变才有效。通常认为，这些疫苗诱导的CD 8 T细胞可能提供某种程度的急性期病毒复制控制，然后减少慢性期的病毒复制。事实上，有相当多的证据表明，这可以在接种疫苗的恒河猴中实现。 越来越多的数据还表明，疫苗诱导的CD 8 T细胞可以防止艾滋病病毒的慢性期复制。在这项提案中，我们将严格检验CD 8 T细胞可以预防艾滋病病毒感染后慢性期病毒复制的假设。我们将使用一种新的创新疫苗方案诱导CD 8 T细胞，该方案由重组DNA引发，然后是重组黄热病加强，以诱导高频率的经典效应记忆T（TEM）细胞应答，这些应答将集中在免疫显性表位上。然后，我们将通过使用持续复制的重组Rhadinovirus进行最终疫苗接种来维持这些应答。该疫苗方案将诱导和维持高频率TEM，我们将确定这些TEM CD 8 T细胞是否可以在印度恒河猴重复低剂量直肠攻击后控制慢性期病毒复制。 在这项建议中，我们计划实现两个具体目标。在具体的目的1中，我们将用编码Mamu-B *08-和Mamu-B * 17-限制性表位的Vif和Nef的小区域接种六只Mamu-B * 08和六只Mamu- B * 17阳性猕猴，然后用重复低剂量的SIVmac 239攻击它们。在我们的第二个目标中，我们将用Gag、达特和Nef的小区域接种六只Mamu-A*01和六只Mamu-A*02阳性猕猴，并且还用重复的低剂量SIVmac 239攻击它们。我们已经有初步证据表明，这种疫苗方案是有效的，可以减少高剂量SIVmac 239攻击后的病毒复制。 如果这种新的疫苗方案能阻止SIV的慢性期复制，这将为HIV疫苗研究开辟一个全新的竞技场。

DESCRIPTION: The induction of HIV-specific broadly reactive neutralizing antibodies by vaccination is the ultimate goal of the HIV vaccine field. There have been encouraging recent reports of the isolation of neutralizing antibodies from HIV-infected individuals. However, it is now clear that these antibodies require considerable somatic mutation to evolve into effective neutralizing antibodies. Induction of these neutralizing antibodies by vaccination, therefore, remains one of the key challenges of the field. In contrast to neutralizing antibodies, we already know how to induce HIV-specific CD8 T cells by vaccination. Furthermore, the T cell receptors (TCRs) expressed by these antigen-specific CD8 T cells do not require somatic mutation to be effective. It is generally thought that these vaccine-induced CD8 T cells might provide some measure of control of acute phase viral replication and then reduce viral replication in the chronic phase. Indeed, there is considerable evidence that this can be achieved in vaccinated rhesus macaques. Accumulating data also suggests that vaccine-induced CD8 T cells can prevent chronic phase replication of the AIDS virus. In this proposal, we will rigorously test the hypothesis that CD8 T cells can prevent chronic phase viral replication after infection with the AIDS virus. We will induce CD8 T cells using a new, innovative vaccine regimen consisting of a recombinant DNA prime, followed by a recombinant Yellow Fever boost to induce high frequency classical effector memory T (TEM) cell responses that will be focused on immunodominant epitopes. We will then maintain these responses with a final vaccination with a continually replicating recombinant Rhadinovirus. This vaccine regimen will induce and maintain high frequency TEM and we will determine whether these TEM CD8 T cells can control chronic phase viral replication after repeated low dose rectal challenge of Indian rhesus macaques. In this proposal we plan to carry out two specific aims. In specific aim one, we will vaccinate six Mamu-B*08 and six Mamu-B*17 positive macaques with small regions of Vif and Nef encoding Mamu-B*08- and Mamu- B*17-restricted epitopes and then challenge them with repeated low doses of SIVmac239. In our second aim, we will vaccinate six Mamu-A*01 and six Mamu-A*02 positive macaques with small regions of Gag, Tat and Nef and also challenge them with repeated low doses of SIVmac239. We already have preliminary evidence that this vaccine regimen is effective and can reduce viral replication after a high dose SIVmac239 challenge. Should this new vaccine regimen prevent chronic phase replication of SIV, this would open up an entirely new arena of HIV vaccine research.