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: 10269042
• 负责人: Ronald S. Veazey
• 金额: $ 82.16万
• 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/10269042
• 关键词: Acute; Adenoviruses; Adjuvant; Affect; Animals; Antibodies; Antibody Response; Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Chronic; Collaborations; 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; Lead; Link; Macaca; Mediating; Mucous Membrane; Mutation; Pathogenicity; Peptides; Primate Retrovirus; Primates; Protein Isoforms; Proteins; Public Health; Publishing; Research; Rodent; SIV; Serotyping; Structure; System; T-Cell Activation; Testing; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Design; Vaccines; Variant; Viral; Viremia; Virus; Virus Diseases; Virus Replication; acute infection; antigen-specific T cells; antiretroviral therapy; base; 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 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.

摘要： 该提案旨在测试一种新的假设和预防艾滋病毒疫苗的方法。我们最近 证明了使用辅助抗原对抗致病性SIVmac 251攻击的感染的功效 疫苗和MHC-II呈递系统。最初我们提出通过使用一种新的创新疫苗 设计完全基于保守的辅助抗原，和一种新的MHC载体系统，我们可以 保护免受SIV感染。我们单独使用这些辅助抗原的成功 值得注意的是，尽管接种了疫苗，但仍有4/6的动物最终被感染。然而，我们现在 我已经积累了证据，证明我们唯一的错误是将达特纳入了最初的疫苗中，我们现在怀疑 在急性感染中大量产生，以“诱骗”和阻碍最初的免疫， 对感染的反应，以及诱导促炎和1型免疫反应， 通过扩增成功治疗所需的靶细胞， 艾滋病病毒的传播，并用尽或消除最敏感的结构抗原特异性T细胞 前体这一假说不仅解释了艾滋病毒感染是如何发生的， 大量的T细胞激活，这也解释了为什么感染导致慢性免疫激活，为什么疫苗 对Gag、达特或Env的反应不可避免地无效，这也是为什么免疫系统不能重新获得免疫应答的原因。 控制艾滋病毒感染，无论是自然或长期抗逆转录病毒治疗后。如果我们的假设正确， 这可能会改变教条，并可能导致有效的疫苗。我们的科学前提是 先前的候选疫苗之所以失败，主要是因为针对早期和大量的 产生的Gag、Env和达特对宿主有害，并且事实上支持病毒复制，因为它们 促进支持这种CD 4 + T细胞嗜性病毒感染的促炎反应，并诱导 对不相关抗原的初级免疫应答。在这里，我们建议完全使用 非“交叉呈现”的亚优势抗原和抗原片段（Rev、Vpr、Vif和保守抗原） 环境区域）使用创新的MHC-II介绍策略进行介绍，因此未用尽或 在急性感染期间导致过度炎症，可能会克服这些病毒机制， 一种可以有效对抗所有HIV分支和毒株的保护性疫苗。