Vaccination with invariant MHC-II-linked accessory antigens for protection from HIV infection

使用不变的 MHC-II 相关辅助抗原进行疫苗接种，以预防 HIV 感染

• 批准号: 10687874
• 负责人: Ronald S. Veazey
• 金额: $ 83.47万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687874
• 关键词: Acute; Adenoviruses; Adjuvant; Affect; Animals; Antibodies; Antibody Response; Antigen Presentation; Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Collaborations; Cross Presentation; Data; Dose; Epitopes; Focal Infection; Genes; HIV; HIV Infections; HIV vaccine; Human; Immune response; Immune system; Immunity; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; International; Link; Macaca; Mediating; Mucous Membrane; Mutation; Pathogenicity; Peptides; Primate Retrovirus; Primates; Protein Isoforms; Proteins; Public Health; Publishing; Rectum; Research; Rodent; SIV; Serotyping; System; T-Cell Activation; Testing; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Design; Vaccinee; Vaccines; Variant; Viral; Viremia; Virus; Virus Diseases; Virus Replication; acute infection; antigen-specific T cells; antiretroviral therapy; breakthrough infection; chronic infection; design; env Gene Products; exhaust; exhaustion; experimental study; gag Gene Products; immune activation; improved; innovation; invariant chain; novel; novel vaccines; pathogenic virus; prevent; recruit; rectal; response; success; transmission process; trial design; vaccine candidate; vaccine efficacy; vaccine platform; vaccine response; vaccinia virus vector; vector; Acute; Adenoviruses; Adjuvant; Affect; Animals; Antibodies; Antibody Response; Antigen Presentation; Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Collaborations; Cross Presentation; Data; Dose; Epitopes; Focal Infection; Genes; HIV; HIV Infections; HIV vaccine; Human; Immune response; Immune system; Immunity; Infection; Infection Control; Inflammation; Inflammatory; Inflammatory Response; International; Link; Macaca; Mediating; Mucous Membrane; Mutation; Pathogenicity; Peptides; Primate Retrovirus; Primates; Protein Isoforms; Proteins; Public Health; Publishing; Rectum; Research; Rodent; SIV; Serotyping; System; T-Cell Activation; Testing; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Design; Vaccinee; Vaccines; Variant; Viral; Viremia; Virus; Virus Diseases; Virus Replication; acute infection; antigen-specific T cells; antiretroviral therapy; breakthrough infection; chronic infection; design; env Gene Products; exhaust; exhaustion; experimental study; gag Gene Products; immune activation; improved; innovation; invariant chain; novel; novel vaccines; pathogenic virus; prevent; recruit; rectal; response; success; transmission process; trial design; vaccine candidate; vaccine efficacy; vaccine platform; vaccine response; vaccinia virus vector; vector

ABSTRACT: This proposal seeks to test a novel hypothesis and approach towards a vaccine to prevent HIV. We recently demonstrated efficacy against infection against pathogenic SIVmac251 challenge using an accessory antigen vaccine and MHC-II presentation system. Initially we proposed that by using a novel and innovative vaccine design based entirely on conserved accessory antigens, and a novel MHC vectored system that we could achieve protection from pathogenic SIV infection. Our success using these accessory antigens alone was remarkable, but not total, as 4/6 animals eventually became infected despite vaccination. However, we now have amassed evidence that our only mistake was to include tat in the original vaccine, which we now suspect is (like HIV env and gag) produced in abundance in acute infection to “decoy” and thwart the initial immune responses to infection, as well as induce pro-inflammatory and type 1 immune response which actually serve to benefit primary and sustained chronic HIV infection by amplifying the target cells necessary for successful HIV transmission, and to exhaust or eliminate the most sensitive structural antigen specific T cell precursors. Not only does this hypothesis explain how HIV infection occurs and is closely followed by a massive T cell activation, it also explains why the infection results in chronic immune activation, why vaccine responses to Gag, Tat, or Env are inevitably ineffective, and also why the immune system cannot regain the control of HIV infection either naturally or after prolonged antiretroviral treatment. If our hypothesis is correct, this may have dogma changing implications and may lead to an effective vaccine. Our scientific premise is that prior vaccine candidates have failed mainly because immune responses directed against early and abundantly produced Gag, Env, and Tat are detrimental to the host, and in fact supportive of viral replication, as they promote proinflammatory responses that support infection with this CD4+ T cell tropic virus, and induce primary immune responses to irrelevant antigens. Here we propose that a vaccine designed entirely using subdominant antigens and antigen fragments that are not “cross presented” (Rev, Vpr, Vif, and a conserved Env region) presented using an innovative MHC-II presentation strategy, and therefore not exhausted or contributing to excessive inflammation during acute infection, may overcome these viral mechanisms, resulting in a protective vaccine that could be effective against all HIV clades and strains.

抽象的： 该提案试图检验一种新的假设和方法，以防止疫苗。我们最近 使用辅助抗原证明了针对病原Sivmac251挑战的效率 疫苗和MHC-II演示系统。最初，我们提出了使用新颖和创新的疫苗 设计完全基于配置的附件抗原和一种新颖的MHC矢量系统，我们可以 保护病原SIV感染。我们仅使用这些附件抗原的成功是 引人注目的但不是总体而言，因为有4/6只动物最终成为被感染的任务疫苗。但是，我们现在 已经积累了证据，表明我们唯一的错误是将tat包括在原始疫苗中，我们现在怀疑 是（如HIV Env和GAG）在急性感染中充分产生的“诱饵”并挫败了初始免疫 对感染的反应，以及诱导促炎和1型免疫响应，实际上使用 通过扩增成功的目标细胞来使原发性和持续的慢性艾滋病毒感染受益 HIV传播，并耗尽或消除最敏感的结构抗原特异性T细胞 前体。该假设不仅解释了HIV感染是如何发生的，而且紧随其后 大量T细胞激活，这也解释了为什么感染会导致慢性免疫激活，为什么疫苗 对插科打，tat或env的反应不可避免地是无效的，也是为什么免疫系统不能保持 自然或长时间抗逆转录病毒治疗对HIV感染的控制。如果我们的假设正确， 这可能会改变教条的影响，并可能导致有效的疫苗。我们的科学前提是 先前的候选疫苗候选者主要是因为针对早期和绝对的免疫调查 产生的插科打,，和tat对宿主有害，实际上支持病毒复制，因为 促进支持这种CD4+ T细胞热带病毒感染的促炎反应，并影响 初级免疫回报与无关的抗原。在这里，我们建议一种完全使用的疫苗 不是“交叉呈现”的亚尺寸抗原和抗原片段（Rev，VPR，VIF和保守 ENV区域）使用创新的MHC-II演示策略提出，因此没有用尽或 急性感染期间导致过量炎症，可能会克服这些病毒机制，导致 在受保护的疫苗中，该疫苗可能有效地抵抗所有艾滋病毒进化枝和菌株。