Seph Borrow: HIV immunology for Vaccine Design
The earliest interactions between HIV and host immune responses have been shown to be critical determinants of the subsequent disease course. Innate responses can be activated very rapidly after infection to contain early pathogen replication and induce the adaptive response. Modulation of innate responses could complement existing HIV vaccine strategies.
Q: Why is it proving so difficult to make an effective HIV vaccine?
We have very effective vaccines for a number of other infections, for example polio or measles virus infections, but the way most of these vaccines work is actually by inducing an immune response, usually a neutralizing antibody response which will help to combat the infection if you subsequently encounter it later in life. Unlike these other pathogens HIV is actually highly resistant to control by the host immune response so the vast majority of people who develop a systemic infection with HIV won't clear that virus, they'll go on to become persistently infected for life; some people may contain the infection better and might take longer to develop the acquired immune-deficiency syndrome or AIDs which is associated with HIV infection but they won't eradicate the infection. This is because HIV is very resistant to host defenses in particular to control by neutralizing antibodies and because of this, conventional approaches to HIV vaccine design won't work and we need to have other more novel approaches to HIV vaccines.
Q: In the search for a vaccine against HIV what are the current lines of research?
There's a very active research effort going on in the HIV vaccine field and this is not an area in which my group is involved with, aiming to try and understand how you could develop a neutralizing antibody response against HIV; that's going to be very difficult but it's certainly a very worthwhile endeavor because if you could induce a broadly neutralizing antibody response that could block the establishment of infection and provide very effective protection against the infection.
A second line of research that's going on and this is something that my group is involved with, is looking at the idea of inducing a T-cell response that would provide protection against HIV. We know that CD8 T-cells are effector cells that can actually combat HIV replication quite effectively and they act by lyzing virus producing cells and also producing soluble factors that will help to contain the infection. In early HIV infection they are very effective at helping to control virus replication spread but they don't actually manage to eliminate the infection altogether. One of the things we're trying to understand is why is it that T-cells don't do a better job at controlling HIV. There seem to be two main mechanisms involved, one is that the virus can very rapidly change so the T-cells are no longer able to see it. Another is that the T-cells become less effective over time during infection. The other thing we are looking at is in people who naturally are controlling the virus somewhat more effectively, are their differences in their T-cell response to that in the people who don't control the infection very well. And so hopefully by these two lines of approach we can understand what would be the most optimally protective T-cell response and try and use that kind of T-cell response in a vaccine.
And yet a third more novel strategy for HIV vaccines would be to use innate immunity to combat HIV replication.
Q: And what is the contribution of our innate immune system in our fight against HIV?
That's actually one of the questions that we are trying to address. Innate responses are actually the body's first line of defense against infection and they are activated very rapidly after we become exposed to a pathogen. They have two important roles: one is to activate T and B-cell responses that are specific for the infection to combat pathogen replication, and the other thing is to try and limit the replication and spread of the pathogen in the interim while the T and B-cell responses are being expanded. So you can think of your innate immune system as almost like a fire-alarm system in a building: if there's a fire it will become activated and one of the things it will do is to call the fire-brigade and like the T and B-cells that's the professional armed combat for the fire (or infection) and at the same time the fire-alarm system might turn on some kind of sprinklers which would help to control the spread of the fire until the fire-brigade get there and might actually manage to put the fire out all together.
We're trying to understand in HIV infection what role innate responses actually play in directly combating virus infection and we do have some evidence that suggests that some parts of the innate immune system can actually play a very important role in controlling HIV replication; we could potentially make use of that in vaccines and therapeutic strategies. But on the other hand because innate responses are involved in activating the immune system and because HIV replicates within immune system cells, innate responses can also have very detrimental effects promoting virus replication and spread through their general immune activating activities. We will need to be very careful how we employ innate responses with any kind of vaccine or therapeutic strategy.
Q: And could your research lead to a vaccine against HIV?
The work that we are doing on T-cells has very obvious applications to HIV vaccine design. Vaccines are being developed at the moment to induce T-cell responses to HIV and our research could enable these vaccines to be tailored in specific ways to induce an optimally protective T-cell response. There are various ways in which innate responses could be employed to combat HIV infection; for example, if we define an innate factor which is involved in mediating protection against HIV that could be incorporated into a microbicide to try and prevent acquisition of HIV infection. Or it could potentially be applied therapeutically to people who are already infected with HIV. I think what's more controversial at the moment is whether you could actually employ innate responses as an effect mechanism in the design of a vaccine. The way vaccines work is by inducing a memory immune response; we know that T and B cells possess the characteristics of memory: once they've encountered an infection once, they'll respond to it much more effectively and provide better protection the second time around. Classically it's been thought that innate responses don't possess this characteristic of memory, but there have been some more recent studies which have suggested that maybe innate responses can exhibit memory and that's something we're quite actively looking at at the moment. And if innate responses do exhibit some form of memory and could be used in a vaccine that could have very broad implications, not just for vaccines for HIV but for other infections too.
Q: And how does your research fit into translational medicine within the department?
There are many other groups within the department who are actively involved in producing and testing candidate vaccines for a wide range of other infections, for example malaria or tuberculosis. And in fact some of the groups are actually generating vaccines for HIV as well. So any findings that we come up with from our research can be very rapidly translated into HIV vaccine design. Not only potentially for HIV but for some of the other infections as well.