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

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，而且每年全世界有超过100万人新感染这种病毒。艾滋病毒疫苗设计的主要障碍之一是艾滋病毒-1在感染者中很少产生与长期控制病毒有关的免疫反应，而不需要定期服用抗艾滋病毒药物。我们正在提出一种基于研究HIV-2的新策略，HIV-2是一种与HIV-1密切相关的病毒，它导致了全球范围内的HIV流行。与HIV-1不同的是，HIV-2只在西非人类最初感染猴病毒（SIVsmm）的地区传播到非常有限的数量，感染HIV-2的总人数似乎在下降，而不是像HIV-1那样不断增加。此外，很大一部分HIV-2感染者（在之前的一项研究中为37%）即使没有接受治疗也不会生病，而且血液中的病毒水平非常低。西非的一项研究表明，如果感染艾滋病毒-2的人随后感染了艾滋病毒-1，与以前没有感染过艾滋病毒-2的新感染艾滋病毒-1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所产生的免疫反应对HIV-1的疾病进展具有一定的保护作用，因此可能有助于制定疫苗和免疫治疗策略。以HIV-2感染作为我们的模型，我们计划研究免疫系统能够在自然控制病毒的人身上识别的一些病毒蛋白质的关键特征。这个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好几年。我们现在希望借此机会建立这些合作，目的是努力开发一种新的艾滋病毒疫苗。这个英国小组多年来一直在西非研究hiv -2感染者的免疫反应和病毒特征。日本的研究小组研究病毒蛋白的结构，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。他们共同努力，希望发现HIV-2蛋白对人体免疫系统是什么样子的，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产生更强、更有效的免疫反应。我们计划确定可以开发为候选疫苗的蛋白质，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”。如果这些看起来很有希望，它们可以由英国和日本的疫苗团队进一步开发。

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.