Natural Killer Cells as Effectors in HIV Cure Strategies

Antiretroviral therapy (ART) has resulted in the life expectancy of HIV infected individuals no longer being significantly less than uninfected people. However, ART must be taken daily, has side effects and comes with significant financial costs. This has placed renewed emphasis on curing HIV. The barrier to a cure is a population of infected cells termed the reservoir, that remain invisible to both therapy and the immune system.

Recent studies have shown that patients treated early in the course of HIV infection have lower viral reservoirs, and some can control viral replication after stopping ART for long periods of time. This is termed 'post treatment control' (PTC), and is a form of remission from HIV infection. If we understand it, PTC may help us find a cure for HIV. As of yet, we cannot predict which patients will and will not become post-treatment controllers. Some data suggests that a type of immune cell - called a Natural Killer (or 'NK') cell - might play an important role in this phenomenon.

In this study, we will use two large cohorts of HIV infected patients who started ART early in infection (called SPARTAC and HEATHER) to determine if characteristics of NK cells can affect reservoir size, how to predict patients who will control viral replication off therapy, and find out how early ART will affect NK cell function. If we can find out how NK cells may help induce control of the virus, such that treatment can be stopped for a while, this will help us plan new treatments as we search for a cure for HIV infection.

Antiretroviral therapy (ART) successfully controls viral replication but is not a cure for HIV infection. ART requires daily medication (with significant financial costs), has side effects, and patients on ART still face higher risks of various morbidities than uninfected patients. Recent evidence from the VISCONTI cohort suggests a subset of patients treated early in infection can successfully control viraemia for a long period of time following ART cessation. Understanding this phenomenon could help generate therapeutic approaches to reduce the reservoir and guide the design of HIV cure clinical trials where ultimate efficacy will require taking patients off ART. Preliminary data from the VISCONTI cohort suggests that NK cells might play a role in PTC while the role of NK cells on reservoir size in patients on early ART has yet to be studied.

Therefore, we will use samples from two large clinical cohorts of primary infected HIV patients - SPARTAC and HEATHER. The SPARTAC trial randomized patients into one of three arms: no ART (standard of care), 24 weeks of ART, and 48 weeks of ART followed by a scheduled treatment interruption. The HEATHER cohort is the largest cohort of primary infection in the UK with longitudinal samples from patients over time. Additionally, 20 patients in the HEATHER cohort will undergo a scheduled intensively monitored treatment interruption in the PITCH study.

In this application, we will use samples from these 3 studies to examine the phenotype and function of NK cells to determine if NK cells can affect the size of the reservoir, the time to viral rebound in patients who stop ART, and the effect of early ART on NK function.

The research in the proposal will characterize the relationship between NK cells and reservoir size and post treatment control (PTC)/time to viral rebound post treatment interruption, and analyze the functionality of NK cells in early treated ART patients over time. This work will potentially identify markers of PTC that could identify who might control viraemia for long periods of time after stopping ART.

1. Who will benefit from this research

1.1) Commercial sector i.e. pharmaceutical industry
1.2) Clinical trials units
1.3) Policy makers, e.g. Public Health England
1.4) Healthcare providers, e.g. the NHS
1.5) HIV-infected patients

2. How will they benefit from this research?

2.1) The pharmaceutical industry is interested in a cure for HIV, evidenced by their recent investment (GSK £20,000,000) into a cure center in University of North Carolina, USA. This work would benefit them in two major ways. First, the research might open up a new class of cells to clear a reactivated viral reservoir (NK cells) if they are shown to have a major impact on reservoir size or PTC. Additionally, if NK cell characteristics are shown to impact PTC, industry could use this information when designing their clinical trials especially in terms of a structured treatment interruption where any markers of successful PTC would be of use. A safe treatment interruption would also be the most effective way of evaluating clinical trials for HIV cure.
2.2) Clinical trials units would also benefit from the identification of cell/markers responsible for PTC as this would aid clinical trial design and affect which clinical markers are measured in patients during HIV cure studies.
2.3) Policy makers would be interested in the results of the proposed studies particularly if a subset of patients can be taken safely off ART, which would potentially affect treatment guidelines. Additionally, our results could also guide funding directions in HIV cure studies. This would not be an immediate effect as many clinical studies would be needed to confirm any biomarkers we might find.
2.4) Healthcare providers would be interested in our data as the cost of ART is high (lifetime treatment £361,000) and being able to safely take patients off ART would be cost effective.
2.5) HIV-1 infected patients would benefit from our research for several reasons. Many are interested in cure studies and our research would aid in their design and direction. Additionally, allowing some patients to safely stop ART would free patients from taking medication daily. This is also a long-term benefit as our results would have to be vigorously tested before allowing patients to stop ART.