MICA: RIVER - Recent HIV Infection Viral Eradication Research

Although treatment with antiretroviral therapy (ART) for HIV infection has markedly changed the life expectancy of people living with HIV, ART alone is unable to cure infection. This is because the virus is able to remain 'dormant' or latent for the life time of the infected person in certain cells of the body called the reservoir. It is for this reason that if ART is stopped the virus returns.

Researchers have recently identified certain very rare individual cases where it appears that HIV has in fact been to some extent "cured", through either very complicated treatment or very early ART at the time of birth.

In this study we will test whether starting ART as soon as an individual has become infected with HIV, followed by an HIV specific vaccination to strengthen the immune responses to HIV and another drug that forces virus out of the latently infected "reservoir" cells, may work in combination to reduce the number of latently infected cells. Research has shown that the fewer cells that contain 'latent viral infection' the better the chance the immune system has to control virus dividing without needing lifelong ART.

In the first place this study will test whether the combination of interventions in very recent HIV infection has the ability to make a significant reduction on the size of the viral reservoir; this is called a 'proof of concept' study and if effective may the lead onto further research.

Antiretroviral therapy (ART) has revolutionised survival in HIV infection; however, alone, ART is unable to eradicate the virus because of an inaccessible pool of infected cells in which the virus is transcriptionally silent (the proviral reservoir).Eradication of HIV from reservoirs is likely to require at least two interventions: 1) Transcriptional activation of HIV from latently infected cells, 2) elimination of these re-activated cells.

We believe that Primary HIV Infection (PHI) represents the optimal timing for reservoir perturbation - the proviral reservoir is less established than in chronic disease, likely to be more susceptible to intervention and relatively homogeneous with limited time to incorporate viral escape mutations from the comparatively well preserved immune responses.

In vitro studies showed that Histone Deacetylase Inhibitor (HDACi) agents such as Vorinostat, Panobinostat and Romidepsin target specific histones associated with HIV repression leading to activation of viral transcription. Data from a single dose and 14-day dosing of vorinostat in HIV+ individuals with chronic infection on ART showed that HDACi led to a 5-fold and 2.5-fold increase in viral transcription, respectively. However, critically, neither study reported elimination of reactivated cells. Therefore, as an adjunct to HDACi administration, we propose an immunisation strategy to stimulate HIV-specific responses that will recognise and kill re-activated "reservoir cells". We will use a prime-boost immunisation with recombinant replication-defective chimpanzee adenovirus and modified vaccinia Ankara vaccines carrying conserved HIV sequences, previously demonstrated to induce high levels of HIV-specific, cytotoxic CD8+ T-cells.

This proof-of-concept study will test the hypothesis that a combination of HDACi-induced transcriptional activation, and potent HIV-specific T-cell immunisation at PHI, under ART suppression, will significantly reduce the proviral reservoir.

Antiretroviral therapy (ART) has revolutionised survival in HIV infection. However, ART alone is unable to eradicate the virus because of an inaccessible pool of HIV infected cells in which the virus is transcriptionally silent (the proviral reservoir). In 2013, there will be >100,000 people living with HIV in the UK, costing >£1 billion annually. These costs are unsustainable. The most desirable goal both for individual patients and society is to understand how to eradicate HIV from the body.

Who will benefit from this research?
This research will benefit the academic community and people living with HIV (PLWH) for which a cure would represent an unprecedented step forward at times where treatment is a lifelong undertaking associated with toxicity and risk of resistance requiring treatment switch. In addition, in the absence of replicating virus the risk of onward viral transmission to sexual partners and infants would also be removed with a direct impact on the epidemic at population level. Hence, this research has the potential to benefit society at large by potentially impacting HIV incidence, as well as removing the burden of care provision for PLWH.

How will they benefit from this research?
Academic Community
Several approaches have been tested in a search for an HIV cure but none has yet been able to eradicate the reservoir of virus using scalable interventions. The study will be the first to investigate a combination approach and will provide critical information about the potential of HDACi accompanied by an immune stimulation. It is clear already that interruption of viral latency will require more than ART and HDACi and even a negative result from this proof of concept study will significantly move the field forwards.
Refinement of ultra low copy HIV viral load measurement and quantification of the HIV reservoirs using new technology represents an invaluable resource for the scientific community working on elucidating the mechanism by which a cure could be developed. These technologies can then be used in other intervention trials.
The collaborators have many years of successful internationally renowned experience in the field of HIV therapeutics, vaccine and prevention. This project will add to the continuation of their expertise as well as maintaining their training and development.

HIV infected community
The participants will have an opportunity to be involved in state-of-the-art study in an innovative area of research. Through community advisory board and interactions with patient groups, this will allow for public education and the research dissemination. Should the approach deliver a functional cure, the study participants would be the first beneficiaries of a long sought after therapy. Further, a cure would limit the known complications associated with continued HIV-mediated immune activation such as malignancy and cardiovascular disease. This would represent a significant alteration in quality of lifestyle, long-term clinical outcome and may confer a significant impact on HIV incidence at a population level.

National Health Services
A functional cure would have a direct impact on the cost associated with the management of PLWH and associated pathologies such as cardiac diseases, cancer and neurocognitive disorders.
The research will provide a basis for clinical decision making and policy-making for governments, policy-makers and advocates to develop evidence-based policies and advocacy aiming at prioritising investments in HIV research (clinical and basic science), allowing for an efficient use of limited funds, supporting research that has a greater potential to deliver results at population level.

Timescales for the benefits to be realised
The results could lead to a Phase 2 Trial within 2 years of completion.
Biological Samples collected during the study will contribute to a biobank that can be made available as soon as the study is completed for future investigation