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

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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.