Targeting mTOR and CD40 Pathways for Adjuvanting HIV Vaccines

靶向 mTOR 和 CD40 通路作为 HIV 疫苗的佐剂

• 批准号: 8519194
• 负责人: Rama Rao Amara
• 金额: $ 307.91万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8519194
• 关键词: AIDS/HIV problem; Adenoviruses; Adherence; Adjuvant; Affinity; Antibodies; Antigens; Antiviral Agents; Avidity; B-Cell Activation; B-Lymphocytes; CCR5 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Country; DNA; DNA/MVA vaccine; Data Analyses; Dendritic Cells; Developed Countries; Development; Electroporation; Failure; Frequencies; Generations; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Human; Humoral Immunities; In Vitro; Individual; Infection; Interferon-alpha; Interleukin-12; Lead; Life; Macaca; Memory; Pathway interactions; Pharmaceutical Preparations; Phase; Production; Resistance; SIV; SIV Vaccines; Sirolimus; Solutions; Structure of germinal center of lymph node; Surface; T-Cell Development; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Testing; Toxic effect; Treatment Protocols; Vaccination; Vaccines; Viral; Viral Vector; Virus; Virus-like particle; base; cost; data management; design; drug resistant virus; immunogenicity; improved; improved functioning; inhibitor/antagonist; mTOR protein; nonhuman primate; novel; novel vaccines; response; safety testing

DESCRIPTION (provided by applicant): Development of an effective HIV vaccine is the long-term solution to control HIV/AIDS world-wide. The failure of adenovirus type 5 based HIV-1 vaccines in humans that was designed to elicit primarily antiviral T cells strongly suggests the need to develop novel vaccine approaches that generate high levels of antiviral T cells with improved function as well as protective antibody. Development of novel adjuvants is necessary to enhance the immunogenicity and efficacy of HIV vaccines. In this HIVRAD, we will use molecules that target mTOR (mammalian target of rapamycin) and CD40 pathways as novel adjuvants to elicit high levels of polyfunctional virus-specific CD8 T cells, CD4 T cells that are resistant to HIV infection and high avidity protective antibody that will lead to enhanced control of HIV infection. This PPG has two projects and two cores. Our project 1 will test the potential of CD40L expressed on the surface of virus-like particles as an adjuvant to enhance the immunogenicity and efficacy of DNA/MVA SIV vaccine. Our project 2 will test the safety, immunogenicity and efficacy of rapamycin (inhibitor of mTOR) as an adjuvant for DNA/MVA SIV vaccine. In addition, we will test for the effects of rapamycin on other replication defective and replication competent viral vectors. Finally, we will test the synergy between inhibiting mTOR and activating CD40 pathways for enhancing the immunogenicity and efficacy of DNA/MVA SIV vaccines. The macaque studies that will be conducted in projects 1 and 2 will be supported by a non-human primate core. An administrative core will provide coordination between projects 1 and 2, and core B, and help with data management and data analyses. RELEVANCE: WHO estimates that there are currently 32 million humans living with HIV/AIDS. Drugs and improved treatment regimens have successfully prolonged the lives of infected individuals in first world countries. However, these are not affordable for the vast majority of HIV-infected individuals. Even in developed nations these are limited by toxicity, affordability, the need for rigorous adherence to therapy and the emergence of drug resistant viruses. Thus, there is a great need to develop a safe and effective HIV vaccine that provides a low-cost, low toxicity solution to long-term control of viral replication - the main goal of this PPG. PROJECT 1: Title: CD40L-Adjuvanted Vaccines for HIV/AIDS Project Leader: AMARA, R PROJECT 1 DESCRIPTION (provided by applicant): The failure of Ad5 based HIV-1 vaccine in humans that is designed to elicit primarily antiviral T cells strongly suggests the need to develop novel vaccine approaches that generate high levels of anti-viral T cells with improved function as well as protective Ab. The goal of this project is to adjuvant the cellular and humoral immunity elicited by our DNA/MVA vaccine that has just entered phase II testing in humans in US. Specifically, we propose to target the CD40 pathway on dendritic cells (DC) and B cells using CD40L. Stimulation of CD40 on DC results in production of IFNa and IL-12 that are critical for generation of highly functional antiviral CD8 response. Activation of B cells through CD40 is necessary for germinal center formation where affinity maturation of B cells occurs leading to generation of high avidity Ab. Here, we will express CD40L on the surface of a SIV virus-like particle (CD40L-VLP). These CD40L-VLPs are potent activators of DC and B cells in vitro. In addition, they can be targeted to DC (through interaction between gpl20 on VLP and CD4 on DC) and allow presentation of Env in its native form that is critical for eliciting broadly cross-reactive neutralizing Ab. In specific aim 1, we will test the potential of CD40L-adjuvanted DNA/MVA SIV vaccine to enhance control of a pathogenic SIV challenge. In addition, we will test whether delivering DNA by electroporation enhances the immunogenicity of the adjuvanted and non-adjuvanted DN/VMVA vaccines. Recent studies from Dr. Rafi Ahmed's lab (PI of project 2) demonstrated that mTOR regulates memory T cell development and inhibition of this pathway following infection or vaccination using rapamycin enhances the magnitude and functional quality of antigen-specific CD8 T cells. Rapamycin has also been shown to down regulate expression of CCR5 on CD4 T cells that results in marked reduction of HIV replication. This could be an added advantage for HIV vaccines, because the vaccine-elicited CCR5' virus-specific CD4 T cells may not be infected by the virus. Essentially we may be reducing the frequency of potential virus target cells while preserving the much-needed CD4 T cell help following infection. In specific aim 2, we will test the synergy between inhibiting mTOR and activating CD40 pathways for adjuvanting the immunogenicity and efficacy of DNA/MVA vaccines. RELEVANCE: WHO estimates that there are currently 32 million humans living with HIV/AIDS. Drugs and improved treatment regimens have successfully prolonged the lives of infected individuals in first world countries. However, these are not affordable for the vast majority of HIV-infected individuals. Even in developed nations these are limited by toxicity, affordability, the need for rigorous adherence to therapy and the emergence of drug resistant viruses. Thus, there is a great need to develop a safe and effective HIV vaccine that provides a low-cost, low-toxicity solution to long-term control of viral replication - the main goal of this PPG.

描述（由申请人提供）：开发有效的艾滋病毒疫苗是控制全球艾滋病毒/艾滋病的长期解决方案。旨在主要引起抗病毒T细胞的人类腺病毒5型HIV-1疫苗的失败表明，需要开发新型疫苗方法，从而产生具有改善功能和保护性抗体的高水平的抗病毒T细胞。为了增强HIV疫苗的免疫原性和功效，新型佐剂的发展是必要的。在此Hivrad中，我们将使用靶向MTOR（雷帕霉素的哺乳动物靶标）和CD40途径的分子作为新型佐剂，以引起高水平的多功能病毒特异性CD8 T细胞，CD4 T细胞，CD4 T细胞，抗HIV感染和高具有抗性抗体的保护性抗体可增强HIV感染。该PPG有两个项目和两个核心。我们的项目1将测试在病毒样颗粒表面表达的CD40L作为辅助物，以增强DNA/MVA SIV疫苗的免疫原性和功效。我们的项目2将测试雷帕霉素（MTOR的抑制剂）作为DNA/MVA SIV疫苗的辅助物的安全性，免疫原性和功效。此外，我们将测试雷帕霉素对其他复制有缺陷和复制竞争的病毒载体的影响。最后，我们将测试抑制MTOR和激活CD40途径之间的协同作用，以增强DNA/MVA SIV疫苗的免疫原性和功效。将在项目1和2中进行的猕猴研究将由非人类灵长类动物核心支持。行政核心将在项目1和2和核心B之间提供协调，并帮助数据管理和数据分析。 相关性：谁估计目前有3200万人患有艾滋病毒/艾滋病。药物和改善的治疗方案已成功延长了第一世界国家感染者的寿命。但是，对于绝大多数受艾滋病毒感染的人来说，这些都是不起作用的。即使在发达国家中，这些也受到毒性，负担能力，严格遵守治疗的需求以及耐药性病毒的出现的限制。因此，非常需要开发一种安全有效的HIV疫苗，该疫苗为长期控制病毒复制提供了低成本，低毒性解决方案 - 该PPG的主要目标。 项目1： 标题：艾滋病毒/艾滋病的CD40L辅助疫苗 项目负责人：Amara，R 项目1描述（由申请人提供）：人类中基于AD5的HIV-1疫苗的失败，旨在引起主要抗病毒药T细胞的强烈表明需要开发新型的疫苗方法，从而产生高水平的抗病毒T细胞具有改善功能以及保护性AB以及保护性AB。该项目的目的是辅助由我们的DNA/MVA疫苗引起的细胞和体液免疫，该疫苗刚刚进入了我们的人类II期测试。具体而言，我们建议使用CD40L靶向树突状细胞（DC）和B细胞上的CD40途径。 DC对CD40的刺激导致IFNA和IL-12的产生，这对于高度功能性抗病毒药CD8反应至关重要。 B细胞通过CD40激活对于B细胞的亲和力成熟而导致高发性AB产生的生发中心形成是必需的。在这里，我们将在SIV病毒样粒子（CD40L-VLP）的表面上表达CD40L。这些CD40L-VLP是体外DC和B细胞的有效活化剂。此外，它们可以针对DC（通过VLP上的GPL20和DC上的CD4之间的相互作用），并允许以其天然形式呈现ENV，这对于引起广泛的交叉反应性中和AB至关重要。在特定目标1中，我们将测试CD40L辅助DNA/MVA SIV疫苗的潜力，以增强对病原SIV挑战的控制。此外，我们将测试通过电穿孔传递DNA是否增强了佐剂和非辅助DN/VMVA疫苗的免疫原性。拉菲·艾哈迈德（Rafi Ahmed）博士实验室（项目2的PI）的最新研究表明，使用雷帕霉素在感染或疫苗接种后，MTOR调节记忆T细胞的发育并抑制该途径，从而增强了抗原特异性CD8 T细胞的幅度和功能质量。雷帕霉素也已显示可降低CCR5在CD4 T细胞上的表达，从而显着减少HIV复制。这可能是HIV疫苗的额外优势，因为疫苗吸收的CCR5病毒特异性CD4 T细胞可能不会被病毒感染。本质上，我们可能正在减少潜在病毒靶细胞的频率，同时保留感染后急需的CD4 T细胞帮助。在特定的目标2中，我们将测试抑制MTOR和激活CD40途径之间的协同作用，以辅助DNA/MVA疫苗的免疫原性和功效。 相关性：谁估计目前有3200万人患有艾滋病毒/艾滋病。药物和改善的治疗方案已成功延长了第一世界国家感染者的寿命。但是，对于绝大多数受艾滋病毒感染的人来说，这些都是不起作用的。即使在发达国家中，这些也受到毒性，负担能力，严格遵守治疗的需求以及耐药性病毒的出现的限制。因此，非常需要开发一种安全有效的HIV疫苗，该疫苗为长期控制病毒复制提供了低成本，低毒性的解决方案 - 该PPG的主要目标。

项目成果

Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut.

• DOI: 10.4049/jimmunol.1501243
• 发表时间: 2015-11-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Chamcha V;Jones A;Quigley BR;Scott JR;Amara RR
• 通讯作者: Amara RR

Codelivery of Envelope Protein in Alum with MVA Vaccine Induces CXCR3-Biased CXCR5+ and CXCR5- CD4 T Cell Responses in Rhesus Macaques.

• DOI: 10.4049/jimmunol.1500083
• 发表时间: 2015-08-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Iyer SS;Gangadhara S;Victor B;Gomez R;Basu R;Hong JJ;Labranche C;Montefiori DC;Villinger F;Moss B;Amara RR
• 通讯作者: Amara RR