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

疫苗诱导的 CD8 T 细胞能否阻止慢性期艾滋病病毒复制？

基本信息

批准号：
8976140
负责人：
David I Watkins
金额：
$ 53万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8976140
关键词：
Acute Alleles Antibodies Antigens Area Attenuated CD8B1 gene Chronic Phase Cytomegalovirus Data Development Dose Epitopes Failure Frequencies Future Goals HIV HIV Vaccine Trials Network HIV vaccine Health Human Immune response Immunity Immunodominant Epitopes Individual Infection Interferons Intravenous MHC Class I Genes Macaca Macaca mulatta Mamu-A 02 antigen Measures Memory Outcome Phase Property RNA Recombinant DNA Recombinants Regimen Reporting Resistance Rhadinovirus SIV Somatic Mutation T cell response T-Cell Receptor T-Lymphocyte Testing Thinking Vaccinated Vaccination Vaccine Design Vaccine Research Vaccines Virus Replication Yellow Fever base design enzyme linked immunospot assay innovation neutralizing antibody novel vaccines prevent recombinant adenovirus rectal research study response terminally differentiated effector memory (TEM) T cells

项目摘要

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.

描述：通过疫苗接种诱导产生 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道称，从艾滋病毒感染者身上分离出了中和抗体。然而，现在很清楚，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，我们已经了解如何通过疫苗接种诱导 HIV 特异性 CD8 T 细胞。此外，这些抗原特异性 CD8 T 细胞表达的 T 细胞受体 (TCR) 不需要体细胞突变即可发挥作用。人们普遍认为，这些疫苗诱导的 CD8 T 细胞可能提供某种控制急性期病毒复制的措施，然后减少慢性期病毒的复制。事实上，有大量证据表明，在接种疫苗的恒河猴中可以实现这一目标。越来越多的数据还表明，疫苗诱导的 CD8 T 细胞可以预防艾滋病病毒的慢性期复制。在本提案中，我们将严格检验 CD8 T 细胞可以阻止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 CD8 T 细胞，该方案包括重组 DNA 引发剂，然后是重组黄热病加强剂，以诱导高频经典效应记忆 T (TEM) 细胞反应，该反应将集中于免疫显性表位。然后，我们将通过使用持续复制的重组鼻病毒进行最终疫苗接种来维持这些反应。这种疫苗方案将诱导并维持高频 TEM，我们将确定这些 TEM CD8 T 细胞在印度恒河猴反复低剂量直肠攻击后是否能够控制慢性期病毒复制。在这项提案中，我们计划实现两个具体目标。在具体目标一中，我们将用编码 Mamu-B*08 和 Mamu-B*17 限制性表位的 Vif 和 Nef 小区域对六只 Mamu-B*08 和六只 Mamu-B*17 阳性猕猴进行疫苗接种，然后对它们进行挑战重复低剂量 SIVmac239。在我们的第二个目标中，我们将为六只 Mamu-A*01 和六只 Mamu-A*02 阳性猕猴接种 Gag、Tat 和 Nef 小区域的疫苗，并用重复低剂量的 SIVmac239 来挑战它们。我们已经有初步证据表明这种疫苗方案是有效的，并且可以在高剂量 SIVmac239 攻击后减少病毒复制。如果这种新的疫苗方案能够阻止 SIV 的慢性期复制，这将为 HIV 疫苗研究开辟一个全新的领域。