MICA: ERADICATE HIV-1: TARGETING THE HIV-1 RESERVOIR WITH NEW IMMUNOTHERAPEUTIC STRATEGIES

There is no cure or vaccine for HIV infection. My aim is to explore new strategies for finding a cure for HIV infection. Thirty four million people are estimated to be infected with HIV - nearly 1% of the global adult population. Of these, 8 million are in receipt of antiretroviral therapy (also called 'ART'), but provision of ART to all who need it is a major logistical and financial challenge. Not only do patients have to stay on therapy for the rest of their lives, but there is the risk of drug resistance, side effects and stigma. We are also starting to learn that patients on ART develop other illnesses - such as heart disease, cancers and early dementia - that we do not fully understand. There is a growing understanding that although current HIV therapies have saved millions of lives, sustaining this for the future may demand new strategies. The most challenging of these is to find a cure for HIV.

HIV spreads widely in the human body in the first days after infection. Upon the use of potent ART the amount of residual virus declines dramatically. However, despite many years of continuous treatment the population of infected cells does not disappear completely - there is a 'reservoir' of infected cells. This tiny but dangerous reservoir of cells has the capacity to grow out and restore the original disease state. If all infected cells could be eradicated this would constitute a cure, but this has only been achieved in one individual and involved the radical step of bone marrow transplantation as well as potent chemotherapy - not a solution applicable to the millions of infected people.

The research will tackle key questions that need to be answered to achieve a cure for HIV. Can we wake up this 'reservoir' of infected cells so that the immune system can attack them? What is the best way to measure the 'reservoir' to assess if a patient might be cured? Are there patients who are more amenable to cure than others - in particular does treatment given very early after infection result in a period of 'remission' in which the patients can stop the drugs without the virus coming back?

The answer to any of these will impact the field significantly. The research will be carried out by Dr John Frater and his team at the University of Oxford, collaborating with researchers across the UK and internationally. The research will be a mixture of laboratory experiments to see how infected cells behave under different conditions and clinical studies in which samples from patients will be tested to try and understand how best to target the reservoir of persisting infected cells.

The studies will be conducted in three related workstreams. In the first, the researchers will study whether cells that contain silenced or 'latent' HIV can be 'woken up' using drugs normally used for cancer and whether the immune system will be able to recognise them. In the second workstream, a new test will be developed for measuring the reservoir using a combination of two techniques - one to measure the amount of viral DNA in the infected cells, and the other to use new genetic technologies to infer whether the viral genes can produce viable replicating viruses. Our aim is to develop and apply the technique, with the potential to bring it into clinical practice. Finally, in the third workstream, the researchers will develop new cohorts of patients treated very early in infection. Early treatment may be a key part of any cure, as the reservoir of infected cells at this stage looks more susceptible to new therapies. By developing these cohorts of adults and children, I aim to provide a platform to do this and conduct tests to see whether a cure might be feasible.

In summary, the research comprises an exciting series of objectives. The need for an HIV cure is great, and if proof-of-principle can be gained in any of these key directions, it would be a major step forward.

There is no cure for HIV infection. The strategy of combining agents to activate the HIV viral reservoir in conjunction with immunotherapy is enticing as the most scalable approach to curing HIV. My aims are to prove the basic scientific justification for this strategy, through 3 key objectives:

1) 'To prove the antigenicity of latently infected cells'. I will expand our data showing that HIV-1 viral protein can be detected in latently-infected resting CD4 T cells, and that the proportion of cells producing protein can be increased using activators of transcription. Using unique immunological reagents - such as affinity-enhanced T cell receptors - I will demonstrate that viral proteins can be presented as antigens, leading to recognition and killing by T cells.

2) 'To develop and apply new assays for accurate measurement of the HIV-1 viral reservoir'. I will approach the problem that there is no gold standard assay that can be broadly applied to the measurement of the reservoir. I will utilise viral sequence data obtained using deep sequencing to infer the 'replication competent' reservoir. I will develop and apply Qualitative Quantitative PCR ('q2PCR' ) using cell lines, primary cell models and ex vivo patient samples.

3) 'To explore the enhanced potential for viral clearance in patients with Primary HIV-1 Infection (PHI)'. PHI is likely to be a critical time when the reservoir is most susceptible to intervention. Using newly established clinical PHI cohorts, I will explore how antiretroviral therapy (ART) when given in PHI - potentially in combination with other agents - might impact viral control and induce a state of remission, or 'post-treatment control'. Understanding PHI - and the impact of ART - would have a major bearing on strategies for eradicating HIV, and for guidelines on improved screening for patients.

The work will be undertaken at a centre with a world-class record in HIV immunology and in collaboration with industry partners.

In the long-term, the research has the potential to impact at the global level, however I will also address the importance of the short- and medium-term objectives. The impact of a cure for HIV on patients, at-risk groups, health-care providers, policy makers, society and governments is clearly enormous. It is the landscape-changing nature of such an achievement that justifies (and demands) undertaking potentially high-risk research. There is a demand for such research from patient groups and representatives (Simon Collins, director of the major patient treatment activist group, i-base, sits on the steering committee of CHERUB) as well as from government (I presented on HIV Cure at a recent Department of Health workshop with the Chief Medical Officer, Dame Sally Davies).

A cure that is applicable to populations still remains years away. However, the proof of concept studies suggested in this proposal are critical and will impact the field and 'users' through the incremental steps in knowledge, methods and process that are required for such an undertaking.

There are 34 million people infected with HIV globally. In the UK around 100,000 individuals are HIV positive and rates of new infection are on the increase again. A cure for these users would allow patients to stop therapy, avoiding the risks of toxicity, drug resistance, stigmatisation and treatment fatigue that can lead to new transmissions and patient morbidity. The wider publicity attracted by cure research also has the impact of maintaining public awareness of HIV infection with the potential for safer sex practices and reduced transmission rates.

HIV costs the National Health Service approximately £1 billion per year. A cure has the potential to confer significant savings, although this will only be proven once the costs of any new treatments are clear.

In the shorter term, this Fellowship will be conducted in collaborations with Merck, Gilead and Adaptimmune, under fully executed Material Transfer Agreements. The commercial potential for using adapted TCRs (Adaptimmune) to target latently infected cells are significant, as are the applications of the drugs Vorinostat (Merck) and Romidepsin (Gilead) for HIV infection.

The development and validation of the q2PCR assay for reservoir quantification has commercial potential in clinical practice as well as the for the development of new bioinformatic pipelines for the analysis of deep-sequencing data and its incorporation into a clinical assay.

The discovery of new antigenic targets on latently infected cells has the potential to impact the HIV vaccine field. I already work closely with academic collaborators in Oxford (Hanke, Dorrell) and Okairos, with an application to the MRC for the REACH trial (under final review), the first proof-of-concept study of HDAC inhibitors plus vaccination in HIV infection. If vaccines can be used to target activated latent cells, this has the potential to open a new direction for HIV vaccination.

The studies of the new cohorts (HEATHER, RESPECT), as well as the already recruited SPARTAC cohort, will potentially impact treatment guidelines and strategies for assaying patients on therapy. If treatment in very early PHI can impact the reservoir and induce a state of 'post-treatment control' (as now suggested in a number of reports), confirmation of this in structured cohorts would impact screening programs to identify patients close to seroconversion, treatment guidelines to start ART as early as possible and assay development to measure the reservoirs (or other yet to be determined markers) in patients with possible induced control, and further assays (eg home testing) to allow regular monitoring of patients off therapy for virological rebound.