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

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.

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.

Impact summary
The main aim of this research proposal is to build on the previous collaborative studies in the structural biology of HIV-2 between our groups in Oxford and Sapporo, focusing on how structural, biophysical and functional information from studies of HIV-2 antigens and other proteins can lead to candidate vaccines to prevent HIV infection. Thus we hope that the long-term impact will be to generate valuable information in a novel strategy for HIV vaccine development.

Another key impact of our project will be to build strong and sustainable interdisciplinary collaborations between researchers in the UK and Japan which will enhance our future research programmes. We have already benefited from the opportunities for researchers in each group to spend time in each other's laboratories and will develop these kind of exchanges more formally as part of this project. This should provide long-term benefits to science in both countries.

In addition, a significant impact of the proposed research will be to increase scientific knowledge about HIV-2 infection. We expect that our work will have broader implications for understanding the way in which retroviruses interact with host proteins and how host immune defences can, in some cases, provide long-term viral control and good clinical outcome. We also hope that the work will provide information about how virus-specific T-cells can control viral replication and what qualities of these T-cells are important for viral control. Although our studies will be carried out in the context of HIV-2 infection, we expect that our data will have more general implications about what makes a good quality and effective T-cell response against retroviruses that can be harnessed in the future for HIV-1 immune-based preventative and immunotherapeutic strategies.

There may be potential clinical applications of these studies for patients with HIV-2 infection, for whom it is often difficult to find optimal antiretroviral therapy (ART). We have already identified the sequences of a few HIV-2-specific T-cell receptors that recognise antigen at unusually low concentrations and plan to characterise further receptors with similar properties. The aim is to generate a panel of HIV-2-specific T-cell receptors that could be transferred into donor cells (which would proliferate and survive better than T-cells from HIV-infected people with disease progression). If the T-cell receptor transduced cells have the same properties as the parent T-cell, and no unwanted cross-reactivity, these could potentially be used in patients with the relevant HLA type as an adjunct to ART. The results of our studies should provide more general information about HIV-2 infection, which should be provided to patients and their clinicians.