Around 2.7 million people became newly infected with HIV in 2010, and a vaccine remains the only realistic way to stop the virus’s spread. The problem is that HIV mutates rapidly, making it nearly impossible for standard vaccines to trigger antibodies that recognise all circulating strains. Even when the body does produce broadly neutralising antibodies, they are difficult for B cells to make without help from specialised T cells called follicular helper T cells. This research tests whether different vaccination strategies can boost those helper T cells, and also tackles a second weakness: the CD8 T cell responses that human vaccine trials have elicited so far are too narrow and too easily escaped by the virus. The team will study why natural infection focuses CD8 T cells on just one or two viral sites, and will evaluate a new Oxford-designed vaccine that targets sites where HIV cannot easily mutate. A third, more speculative aim asks whether natural killer cells—part of the body’s first line of defence—can be trained by vaccination to mount a stronger response on re-exposure. If these approaches work, they could lead to an HIV vaccine that combines antibody, T cell, and NK cell immunity, potentially saving millions of lives each year.
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Around 34 million people worldwide are currently infected with human immunodeficiency virus type 1 (HIV-1), the virus that causes AIDS, and 1.8 million people died of AIDS in 2010. Despite advances in the treatment and prevention of HIV infection, ~2.7 million people became newly-infected with HIV in 2010. A vaccine is therefore urgently needed to combat HIV spread. The goal of this research programme is to contribute to the development of an effective HIV vaccine. The studies below will synergise with complementary HIV vaccine research being carried out by a US-funded international consortium of which the applicants are part. Development of effective HIV vaccines is very challenging. Most vaccines for other virus infections work by inducing the production of antibodies (Abs), proteins that bind specifically to the virus and block the establishment of infection. It is likely that a vaccine that induced Abs capable of neutralising all the circulating strains of HIV (termed broadly-neutralising (bN)Abs ) would be very effective. However HIV is a highly variable virus, which makes it difficult for vaccines to stimulate the production of Abs capable of recognising all HIV variants. Even more importantly, very few of the Abs that bind to HIV are actually able to neutralise the virus and block infection. Recent studies have shown that HIV-1 bNAbs are very difficult for Ab-producing cells (B cells) to make. Specialised helper T cells, termed follicular helper T cells (TFH), provide help to B cells for Ab production. We hypothesise that HIV-specific TFH may therefore be very important for the generation of HIV-1 bNAbs. The first aim of the proposed research will be to test this hypothesis, and to compare the ability of different vaccination strategies to induce TFH activity. Even bNAbs are not likely to be able to block HIV infection in all cases, so it is also important for HIV vaccines to elicit other immune responses that can control virus replication after infection. HIV-specific CD8 T cells play an important role in HIV control, and vaccine-elicited CD8 T cell responses have been shown to contain HIV replication efficaciously in animal models. However the HIV-specific T cell responses elicited in human vaccine trials to date have not been adequate to control virus replication; furthermore HIV was rapidly able to mutate to escape from these responses. The second aim of the proposed research will be to develop strategies to elicit optimally-protective HIV-specific CD8 T cell responses. We will study why the first CD8 T cell responses made in natural HIV infection are often focused on just 1-2 sites in the virus (which is detrimental, as it is much easier for the virus to mutate at 1-2 sites than to escape from responses targeted to many sites), to understand how this can be overcome by vaccination. We will also study the CD8 T cell responses elicited by a new T cell-inducing vaccine developed in Oxford, which has been designed to elicit strong HIV-specific CD8 T cell responses targeted to sites in the virus where HIV is less likely to be able to mutate. We will investigate how specific aspects of the responses induced by this vaccine may enhance or reduce vaccine efficacy, and if required, will design improved T cell vaccines based on our results. Our third aim will be to explore the novel idea of harnessing the activity of natural killer (NK) cells (rapidly-responding cells that form part of the first line of defence against infection) in HIV vaccine design. NK cells contribute to HIV control, but until recently NK cells were not thought to share the ability of B and T cells to mount a more protective response on second exposure to a particular infection, which forms the basis of vaccination. We plan to study whether vaccines can induce long-lasting changes in NK cell responses in humans. We will also analyse how NK cell receptors recognise HIV, so that we can design NK-stimulatory vaccines to combat HIV infection.
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