Development of a Vaccine for HIVAIDS: Cellular Immunity

HIV/艾滋病疫苗的开发:细胞免疫

基本信息

项目摘要

Our HIV vaccine approach is based on initial immunization with a replicating adenovirus (Ad) vector carrying an HIV gene(s) followed by a booster immunization with an HIV envelope protein. The Ad-HIV vaccine replicates in epithelial cells that line mucosal inductive sites, thus eliciting strong, persistent cellular immunity at mucosal effector sites as well as in the blood. We have shown that initial immunizations with an Ad-HIV vaccine also stimulates production of anti-HIV antibodies. Together, the regimen induces strong and durable protective responses. We have demonstrated that administration of Ad-HIV vaccine to the upper respiratory tract as well as to the gut (by oral immunization) elicits memory T cells that possess "homing receptors" leading them to traffic to the intestine, a prime site of HIV infection. Thus the vaccine approach elicits cellular immunity at a location critical for preventing or controlling HIV infection. Recently we have explored several routes of Ad-recombinant immunization in rhesus macaques including intrarectal, intravaginal, and sublingual as well as the standard administration to the upper respiratory tract intranasally or intratracheally. Interestingly, cellular immune responses as maeasured by interferon-gamma ELISPOT and T cell proliferation assays revealed similar levels of imnmune responses were achieved in peripheral blood by all immunization routes. Administration of an Ad-GFP marker recombinant by the various routes also showed the presence of replicating Ad was similar in rectal tissue and the lung without regard to immunization route. The data suggest use of replicating Ad vectors may facilite vaccine delivery by the easiest, least invasive route. The study of NK cells, key effector cells of innate immunity, is also continuing in order to elucidate their response to Ad-HIV vaccine immunization and their cooperation with vaccine-elicited antibodies in mediating cell killing functions such as antibody-dependent cellular cytotoxicity and antibody-dependent cell mediated viral inhibition. Macaque NK cells have been characterized phenotypically by flow cytometry as a prelude to expanded functional studies. New studies have also shown the importance of CD4 T cell responses in assisting NK cell recall responses. Studies have shown that antibody activities mediated by NK effector cells that span innate and adaptive immunity are correlated with reduced viremia following viral challenge of immunized rhesus macaques. Further, new studies on NKT cells and gamma/delta T cells have recently been initiated to investigate a potential role in vaccine-mediated viremia control. We have also examined Th17 cells in vaccinated versus control macaques to determine if a vaccine which is partially protective could preserve this cell population which is important for control of microbial pathogens. We found that unfortunately, strong viremia control elicited by vaccination does not prevent gradual Th17 cell loss. The implication of this finding is that a vaccine which fully confers sterilizing protection will be necessary to prevent disease sequelae. Finally, we have been exploring use of an immune modulator to facilitate induction of cellular immunity following treatment of macaques with anti-retroviral therapy. A comprehensive picture of responses of various cell types is being compiled and will facilitate further design of both prophylactic and therapeutic vaccine regimens. Overall we have developed expanded capabilities to investigate vaccine-elicited cellular immunity by flow cytometry, as well as by expression of various cytokines and chemokines. Our studies continue to show induction of potent cellular immune responses systemically and mucosally following the replicating Ad-recombinant prime/protein boost regimen.
我们的HIV疫苗方法是基于用携带HIV基因的复制型腺病毒(Ad)载体进行初始免疫,然后用HIV包膜蛋白进行加强免疫。Ad-HIV疫苗在粘膜诱导位点的上皮细胞中复制,从而在粘膜效应位点以及血液中引发强烈、持久的细胞免疫。我们已经表明,最初的免疫接种与艾滋病毒疫苗也刺激生产抗艾滋病毒抗体。总之,该方案诱导了强而持久的保护性反应。我们已经证明,Ad-HIV疫苗的管理,上呼吸道以及肠道(通过口服免疫)eliminates记忆T细胞,拥有“归巢受体”,导致他们交通到肠道,艾滋病毒感染的主要网站。因此,疫苗方法在预防或控制HIV感染的关键位置增强细胞免疫。最近,我们已经探索了几种途径的Ad-重组免疫恒河猴,包括直肠内,阴道内,舌下,以及标准的管理上呼吸道鼻内或肠道内。有趣的是,如通过干扰素-γ ELISPOT和T细胞增殖测定所测量的细胞免疫应答揭示了通过所有免疫途径在外周血中实现了相似水平的免疫应答。通过各种途径施用Ad-GFP标记物重组体也显示出复制Ad在直肠组织和肺中的存在是相似的,而不考虑免疫途径。数据表明,使用复制Ad载体可以通过最简单、侵入性最小的途径促进疫苗递送。NK细胞,先天免疫的关键效应细胞的研究也在继续,以阐明其对Ad-HIV疫苗免疫的应答及其与疫苗引发的抗体在介导细胞杀伤功能如抗体依赖性细胞毒性和抗体依赖性细胞介导的病毒抑制中的合作。猕猴NK细胞已通过流式细胞术表征表型,作为扩展功能研究的前奏。新的研究也表明了CD 4 T细胞应答在辅助NK细胞回忆应答中的重要性。研究表明,跨越先天性和适应性免疫的NK效应细胞介导的抗体活性与免疫恒河猴病毒攻击后减少的病毒血症相关。此外,最近开始了对NKT细胞和γ/δ T细胞的新研究,以研究疫苗介导的病毒血症控制中的潜在作用。我们还检查了接种疫苗的猕猴与对照猕猴中的Th 17细胞,以确定部分保护性的疫苗是否可以保留这种对控制微生物病原体很重要的细胞群。我们发现,不幸的是,疫苗接种引起的强病毒血症控制并不能阻止Th 17细胞的逐渐丧失。这一发现的含义是,一种完全提供消毒保护的疫苗对预防疾病后遗症是必要的。最后,我们一直在探索使用一种免疫调节剂,以促进诱导细胞免疫后,猕猴与抗逆转录病毒治疗。正在编制各种细胞类型的反应的全面情况,这将有助于进一步设计预防性和治疗性疫苗方案。总的来说,我们已经开发了扩展的能力,通过流式细胞术以及各种细胞因子和趋化因子的表达来研究疫苗引起的细胞免疫。我们的研究继续显示,在复制性Ad重组初免/蛋白加强方案后,诱导了全身和粘膜的有效细胞免疫应答。

项目成果

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Marjorie Robert-Guroff其他文献

Marjorie Robert-Guroff的其他文献

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{{ truncateString('Marjorie Robert-Guroff', 18)}}的其他基金

VACCINE USING HIV/SIV ENV, GAG, NEF & TAT ADENOVIRUS WITH PROTEIN BOOSTING
使用 HIV/SIV ENV、GAG、NEF 进行疫苗
  • 批准号:
    7958842
  • 财政年份:
    2009
  • 资助金额:
    $ 169.69万
  • 项目类别:
VACCINE USING HIV/SIV ENV, GAG, NEF & TAT ADENOVIRUS WITH PROTEIN BOOSTING
使用 HIV/SIV ENV、GAG、NEF 进行疫苗
  • 批准号:
    7716363
  • 财政年份:
    2008
  • 资助金额:
    $ 169.69万
  • 项目类别:
VACCINE USING HIV/SIV ENV, GAG, NEF & TAT ADENOVIRUS WITH PROTEIN BOOSTING
使用 HIV/SIV ENV、GAG、NEF 进行疫苗
  • 批准号:
    7349364
  • 财政年份:
    2006
  • 资助金额:
    $ 169.69万
  • 项目类别:
VACCINE USING HIV/SIV ENV, GAG, , NEF AND TAT ADENOVIRUS RECOMBINANTS
使用 HIV/SIV ENV、GAG、NEF 和 TAT 腺病毒重组体的疫苗
  • 批准号:
    7165825
  • 财政年份:
    2005
  • 资助金额:
    $ 169.69万
  • 项目类别:
Development of a Vaccine for HIVAIDS: Cellular Immunity
HIV/艾滋病疫苗的开发:细胞免疫
  • 批准号:
    8937942
  • 财政年份:
  • 资助金额:
    $ 169.69万
  • 项目类别:
Development of a Vaccine for HIVAIDS: Cellular Immunity
HIV/艾滋病疫苗的开发:细胞免疫
  • 批准号:
    7733459
  • 财政年份:
  • 资助金额:
    $ 169.69万
  • 项目类别:
Development of a Vaccine for HIV-AIDS: Translation to the Clinic
艾滋病毒/艾滋病疫苗的开发:转化为临床
  • 批准号:
    10014519
  • 财政年份:
  • 资助金额:
    $ 169.69万
  • 项目类别:
Development of a Vaccine for HIVAIDS: Cellular Immunity
HIV/艾滋病疫苗的开发:细胞免疫
  • 批准号:
    9153760
  • 财政年份:
  • 资助金额:
    $ 169.69万
  • 项目类别:
Development of a Vaccine for HIVAIDS: Humoral Immunity
HIV/艾滋病疫苗的开发:体液免疫
  • 批准号:
    8157605
  • 财政年份:
  • 资助金额:
    $ 169.69万
  • 项目类别:
Basic and Applied Studies in Development of an AIDS Vacc
艾滋病疫苗开发的基础和应用研究
  • 批准号:
    7337903
  • 财政年份:
  • 资助金额:
    $ 169.69万
  • 项目类别:

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cGAS-STING 通路靶向具有 CD46 趋向性和 AFP 启动子的复制腺病毒条件性复制限制用于治疗肝细胞癌
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针对间皮瘤中发现的特征基因突变的具有复制能力的腺病毒的分子疗法
  • 批准号:
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    2021
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溶瘤腺病毒和免疫代谢佐剂治疗胶质瘤
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人腺病毒核蛋白核心的结构表征
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禽腺病毒的分子生物学和发病机制
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禽腺病毒的分子生物学和发病机制
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探索营养剥夺对 T 细胞和溶瘤腺病毒的影响,以创造用于肿瘤治疗的免疫激活剂
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Research on detection of novel adenoviruses by genetic methods
新型腺病毒的基因检测研究
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