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

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： 该提案旨在测试预防艾滋病毒疫苗的新假设和方法。我们最近 使用辅助抗原证明对致病性 SIVmac251 攻击的感染具有功效 疫苗和 MHC-II 呈递系统。最初我们建议通过使用一种新颖的创新疫苗 设计完全基于保守的辅助抗原，以及我们可以使用的新型 MHC 载体系统 实现免受致病性 SIV 感染的保护。我们仅使用这些辅助抗原就取得了成功 值得注意的是，但不是全部，因为尽管接种了疫苗，仍有 4/6 的动物最终被感染。然而，我们现在 已经收集了证据表明我们唯一的错误是将tat包含在原始疫苗中，我们现在怀疑这是 在急性感染中大量产生（如 HIV env 和 gag），以“诱骗”并阻碍初始免疫 对感染的反应，以及诱导促炎和 1 型免疫反应，这些反应实际上起到了作用 通过扩增成功所需的靶细胞，使原发性和持续性慢性 HIV 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。这一假设不仅解释了艾滋病毒感染是如何发生的，而且紧随其后的是 大量 T 细胞激活，它也解释了为什么感染会导致慢性免疫激活，为什么疫苗 对 Gag、Tat 或 Env 的反应不可避免地无效，这也是免疫系统无法恢复免疫系统的原因 自然控制或长期抗逆转录病毒治疗后控制艾滋病毒感染。如果我们的假设是正确的 这可能会改变教条，并可能带来有效的疫苗。我们的科学前提是 先前的候选疫苗失败的主要原因是针对早期和大量的免疫反应 产生的 Gag、Env 和 Tat 对宿主有害，而且实际上支持病毒复制，因为它们 促进促炎反应，支持这种 CD4+ T 细胞嗜性病毒的感染，并诱导 对不相关抗原的初级免疫反应。在这里，我们建议完全使用 次优势抗原和非“交叉呈递”的抗原片段（Rev、Vpr、Vif 和保守的 Env 区域）使用创新的 MHC-II 呈现策略呈现，因此不会耗尽或 在急性感染期间导致过度炎症，可能会克服这些病毒机制，从而导致 一种可以有效对抗所有艾滋病毒分支和毒株的保护性疫苗。