Design of HIV vaccines that stimulate T cell and NK cell immunity

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.

This goal of this programme of research is to contribute to the development of an effective vaccine to combat infection with human immunodeficiency virus type 1 (HIV-1). We will focus on cellular immune responses, aiming to design strategies that:
1) Induce CD4 follicular helper T cell (TFH) responses that enhance the generation of HIV-1 broadly-neutralising antibodies
2) Elicit optimally-protective HIV-specific CD8 T cell responses
3) Enhance natural killer (NK) cell-mediated HIV control

We will employ a combination of i. in vitro immunovirological studies; ii. advances in understanding of virus-immune system interactions during HIV infection gained by analysis of unique sample series from subjects acutely-infected with HIV and chronic patients with different clinical outcomes; and iii. insights from detailed analysis of specific aspects of the immune responses elicited in human vaccine trials, to inform the rational design of optimally-effective HIV vaccine immunogens.

Techniques used in the proposed work will include a breadth of cellular and molecular methods for evaluating the phenotype and functions of innate and T cell subsets, including novel assays for analysis of HIV-specific TFH activity, recently-developed methods for evaluation of naïve and pre-immunisation memory T cell repertoires and Nanostring-based gene expression analyses; together with multiple virological, proteomics-based and bioinformatics techniques with which we have expertise in-house strengthened by input from local and international collaborators.

A key element to this proposal is that it will synergise with the new NIH-funded Center for HIV/AIDS Vaccine Immunogen Design, of which the applicants are part, and with other vaccine research ongoing in Oxford. This will facilitate achievement of the objectives above both by providing access to reagents/samples and by supporting complementary studies that add value to the work in this programme.

The main goal of the proposed research is to contribute to the development of an effective vaccine to combat the spread of human immunodeficiency virus type 1 (HIV-1). HIV-1 infection is associated with development of an acquired immunodeficiency syndrome (AIDS) that is almost always fatal if untreated. Around 34 million people worldwide are currently living with HIV, and HIV/AIDS caused ~1.8 million deaths in 2010. Although antiretroviral therapy can reduce virus replication and delay disease progression it does not eradicate infection and needs to be taken for life. This is expensive, and many infected individuals in developing countries where the global HIV burden is highest have little or no access to treatment. An estimated 2.7 million people became newly-infected with HIV in 2010, emphasising the urgent need for a vaccine to block HIV spread.
Availability of an effective prophylactic HIV vaccine would be of direct benefit to individuals at risk of HIV infection, who include young adults in regions with a high HIV prevalence (e.g. parts of sub-Saharan Africa), individuals worldwide with sexual exposure to HIV-infected partners, and babies born to HIV-infected mothers. Even a partly-efficacious HIV vaccine, which could be available for use within 8-10 years, would reduce their risk of HIV infection. Some of our work could also facilitate therapeutic HIV vaccine design, which in a 10-15-year timeframe could benefit individuals already infected with HIV, enabling them to contain infection and preventing disease progression.
In addition to benefiting at-risk individuals, the availability of HIV vaccines would also benefit their families and other members of the local community. The HIV pandemic has had devastating effects on developing countries with high HIV prevalence rates, destroying families, over-burdening the health system and having a severe impact on the economy, living standards and education. Even in developed countries with lower HIV prevalence rates, HIV/AIDS treatment costs constitute a burden on the health system: annual UK HIV treatment and care costs could reach £750 million by 2013. A vaccine that blocked HIV spread would halt the pandemic and in the long-term would relieve its devastating effects.
By enabling the development of a HIV vaccine, our research could also benefit the commercial sector. Vaccine production for large-scale efficacy trials (in 5-8 years time) and subsequent clinical use (in 8-12 years time) by pharmaceutical companies would create jobs and boost the UK economy.

Findings from the proposed research could also help to inform the development of vaccines for other infectious diseases (e.g. malaria, tuberculosis and hepatitis virus infections) and some forms of cancer. In the medium-term (10-15 years) individuals at risk from these diseases could therefore also benefit from our work via the availability of new vaccines. Vaccines are the most cost-effective form of medical intervention for preventing death and disease, and have made a significant contribution to the increase in life expectancy over the last 50 years. The availability of new vaccines will have benefits to society as a whole. It will also reduce the burden on health services, and by increasing the health of the population, benefit the economy. There will also be direct benefits to the commercial sector via creation of small biotech companies to develop new vaccines and the need for vaccine production by the pharmaceutical industry.

During the proposed studies students and postdoctoral staff will receive training in specific research skills, which will be of direct benefit to them and will also enhance the skill base in the UK workforce. By engaging school-children, students and the general public in our research we will also promote interest in and generate support for biomedical research, which will help the UK to remain at the forefront of science and technology, with long-term benefits for the UK economy.