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

摘要： 这项提议旨在测试一种新的假设和方法，以获得预防艾滋病毒的疫苗。我们最近 使用辅助抗原显示了对抗致病性SIVmac251攻击的感染的有效性 疫苗和MHC-II呈递系统。最初，我们提出通过使用一种新的和创新的疫苗 完全基于保守的辅助抗原的设计，以及一种新的MHC载体系统，我们可以 实现对病原性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，尽管接种了疫苗，但仍有四分之四的动物最终被感染。然而，我们现在 已经积累了证据，证明我们唯一的错误是在最初的疫苗中加入了TAT，我们现在怀疑 (如hiv env和gag)在急性感染中大量产生，以“诱饵”和挫败最初的免疫。 对感染的反应，以及诱导促炎和1型免疫反应，这实际上是 通过放大成功所需的靶细胞，使原发和持续的慢性艾滋病毒感染受益 HIV的传播，并耗尽或消除最敏感的结构抗原特异性T细胞 先驱物。这一假说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，这也解释了为什么感染会导致慢性免疫激活，为什么要接种疫苗 对GAG、TAT或Env的反应不可避免地无效，这也是为什么免疫系统无法恢复 自然或在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， 这可能会改变教条的含义，并可能导致有效的疫苗。我们的科学前提是 以前的候选疫苗失败的主要原因是免疫反应针对早期和大量的 产生的Gag、Env和Tat对宿主有害，实际上支持病毒复制，因为它们 促进支持感染这种CD4T细胞嗜性病毒的促炎反应，并诱导 对无关抗原的初级免疫反应。在这里，我们建议设计一种完全使用 亚显性抗原和非“交叉呈递”的抗原片段(REV、VPR、VIF和保守的 环境区域)使用创新的MHC-II演示策略演示，因此没有用尽或 在急性感染期间引起过度炎症，可能会克服这些病毒机制，从而导致 在一种保护性疫苗中，这种疫苗可能对所有艾滋病毒分支和毒株有效。

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.