Structure-based vaccine design: using structural information from HIV-2 to design better HIV-1 immunogens

基于结构的疫苗设计：利用 HIV-2 的结构信息设计更好的 HIV-1 免疫原

• 批准号: MR/S020616/1
• 负责人: Sarah Rowland-Jones
• 金额: $ 62.92万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS020616%2F1
• 关键词: Structure; based; vaccine; design; using

Despite a massive effort from researchers around the world, there is still no effective vaccine that can protect people from HIV infection, and each year well over one million people around the world become newly infected with the virus. One of the main barriers to HIV vaccine design is that HIV-1 only rarely generates immune responses in infected people that are associated with long-term control of the virus without the need to take anti-HIV drugs on a regular basis. We are proposing a novel strategy to develop an HIV vaccine based on studying HIV-2, a virus closely related to HIV-1 which has caused the worldwide HIV epidemic. Unlike HIV-1, HIV-2 has only spread to a very limited amount beyond the area where humans first became infected with what was originally a monkey virus (SIVsmm) in West Africa, and the total number of people infected with HIV-2 appears to be falling rather than relentlessly increasing, as is the case for HIV-1. Moreover, a large proportion of people with HIV-2 infection (37% in one previous study) don't ever get sick, even without treatment, and have very low levels of virus in the bloodstream. One study in West Africa showed that if HIV-2-infected people subsequently became infected with HIV-1, they lived longer and were less likely to progress to AIDS compared to people newly-infected with HIV-1 without previous HIV-2 infection. This could suggest that immune responses generated by exposure to HIV-2 give some protection against HIV-1 progression to disease and could therefore help in strategies for vaccines and immune-based therapy.Taking HIV-2 infection as our model, we plan to study the key features of some of the virus proteins that the immune system is able to recognise in people who are naturally controlling the virus. This project involves a collaboration between two research groups, one in the UK and one in Japan, who have been working with one another for several years. We now want to take the opportunity to build up these collaborations with the aim of trying to develop a new HIV vaccine. The UK group has studied immune responses and the characteristics of the virus in HIV-2-infected people in West Africa for many years. The Japan group studies the structure of viral proteins and how they interact with the host immune system at the level of individual molecules. Working together they hope to discover what HIV-2 proteins look like to the human immune system and why this helps people with HIV-2 to make much stronger and more potent immune responses to HIV-2 than HIV-1-infected people do against HIV-1. We plan to identify proteins that can be developed as vaccine candidates and see if they are "seen" by the immune systems of people naturally infected with HIV-2 and HIV-1. If these look promising, they can be developed further by vaccine teams in the UK and Japan.

尽管世界各地的研究人员付出了巨大的努力，但仍然没有有效的疫苗可以保护人们免受艾滋病毒感染，每年全世界有100多万人新感染艾滋病毒。艾滋病毒疫苗设计的主要障碍之一是，HIV-1很少在感染者中产生免疫反应，这种免疫反应与长期控制病毒有关，而不需要定期服用抗艾滋病毒药物。我们正在提出一种新的策略，以开发一种基于研究HIV-2的HIV疫苗，HIV-2是一种与HIV-1密切相关的病毒，它导致了全球HIV流行。与HIV-1不同的是，HIV-2只在西非人类首次感染猴病毒（SIVsmm）的地区以外传播了非常有限的数量，感染HIV-2的总人数似乎在下降，而不是像HIV-1那样无情地增加。此外，很大一部分HIV-2感染者（在以前的一项研究中为37%）即使没有治疗也不会生病，并且血液中的病毒水平非常低。西非的一项研究表明，如果HIV-2感染者随后感染了HIV-1，与新感染HIV-1但以前没有HIV-2感染的人相比，他们的寿命更长，进展为艾滋病的可能性更小。这可能表明，暴露于HIV-2产生的免疫反应对HIV-1的疾病发展提供了一些保护，因此可能有助于疫苗和免疫治疗的策略。以HIV-2感染为模型，我们计划研究免疫系统能够识别的一些病毒蛋白质的关键特征。该项目涉及两个研究小组之间的合作，一个在英国，一个在日本，他们已经相互合作了几年。我们现在希望借此机会建立这些合作，旨在尝试开发一种新的艾滋病毒疫苗。英国研究小组多年来一直在研究西非HIV-2感染者的免疫反应和病毒特征。日本研究小组研究病毒蛋白质的结构以及它们如何在单个分子水平上与宿主免疫系统相互作用。他们希望通过合作发现HIV-2蛋白对人体免疫系统的作用，以及为什么这有助于HIV-2感染者对HIV-2产生比HIV-1感染者对HIV-1更强、更有效的免疫反应。我们计划鉴定出可以作为候选疫苗开发的蛋白质，并观察它们是否被自然感染HIV-2和HIV-1的人的免疫系统“看到”。如果这些看起来有希望，它们可以由英国和日本的疫苗团队进一步开发。

项目成果

Structure of HIV-2 Nef reveals unique features distinct from HIV-1 involved in immune regulation

HIV-2 Nef 的结构揭示了与参与免疫调节的 HIV-1 不同的独特特征

• DOI: 10.1101/779439
• 发表时间: 2019
• 作者: Hirao K

Delayed disease progression in HIV-2: the importance of TRIM5a and the retroviral capsid.

HIV-2 的延迟疾病进展：TRIM5a 和逆转录病毒衣壳的重要性。

• DOI: 10.1111/cei.13280
• 发表时间: 2019
• 期刊: Clinical and experimental immunology
• 影响因子: 4.6
• 作者: Boswell MT

Structure of HIV-2 Nef Reveals Features Distinct from HIV-1 Involved in Immune Regulation

• DOI: 10.1016/j.isci.2019.100758
• 发表时间: 2020-01-24
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Hirao, Kengo;Andrews, Sophie;Maenaka, Katsumi
• 通讯作者: Maenaka, Katsumi