HIT HIDDEN HIV

Paving the way towards HIV eradication/control

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 Obiettivo del progetto (Objective)

'Major advances in HIV/AIDS treatment regimens have fundamentally altered the natural history of the disease and sharply reduced HIV-related morbidity and mortality in countries where such treatments are accessible. The most notable advance is the use of combination antiretroviral therapy or ART. However, ART is unable to achieve virus eradication or “sterilizing cure”. Indeed, in most cases, viral rebound is observed after ART interruption. Thus, life-long treatment is currently needed to control HIV. Drug resistance, cumulative side effects and high cost, represent major drawbacks of such treatments. The persistence of HIV in treated patients results from the establishment of a viral reservoir insensitive to ART and poorly visible to the immune system. Thus, understanding HIV persistence and developing drugs able to flush out HIV, in order to achieve viral eradication or “sterilizing cure” remain outstanding challenges. Two main lines of research are being proposed. The first starts from the recent discovery by partners of this consortium of the immune-modulator Samhd1 as the cellular factor restricting HIV-1 infection in myeloid cells. We will explore a role for Samhd1 in immune activation and inflammation, and its impact on the balance between viral replication and persistence. To understand further HIV persistence, we will study the molecular mechanisms underlying post-integrative latency. The second aims at identifying and optimizing novel naturally occurring inducers of HIV reactivation. Additionally, a novel non-human primate model will be developed, allowing the study of viral persistence in vivo by tracking latently-infected cells. The project aims at (i) increasing knowledge on the contribution of immune activation and inflammation to HIV persistence (ii) deciphering the cellular and molecular mechanisms of viral persistence (iii) translating this basic knowledge into novel targets to achieve a cure for HIV/AIDS.'

Introduzione (Teaser)

HIV persistence is a significant medical challenge of modern times. A better understanding of HIV latency is thus required to achieve a functional cure for infected people.

Descrizione progetto (Article)

Over the years, HIV research efforts have managed to reduce mortality by successfully controlling viral load and replication. However, highly active antiretroviral therapy (HAART) cannot eradicate the virus, and viral rebound is observed after treatment interruption. As a result, lifelong treatment is required to control HIV replication and is associated with significant side-effects, including drug resistance.

The persistence of HIV in treated patients stems from the inability of the immune system to detect the remaining viral reservoir that is insensitive to therapy. As a result, the EU-funded 'Paving the way towards HIV eradication/control' (http://www.hithiddenhiv.org (HIT HIDDEN HIV)) project aims to understand how HIV persists and to find ways to achieve complete viral eradication. The key objectives are to elucidate the process of latency and also discover ways to reactivate latent HIV.

Research into the basic mechanisms of HIV post-integrative latency has identified cellular factors (NELF, integrator) that work to repress HIV-1 transcription. Inhibition of these proteins should allow transcriptional reactivation of the virus, an approach that could be exploited therapeutically.

Another part of the project has focused on the recently identified SAMHD1 immune modulator as the cellular factor restricting HIV-1 infection in myeloid cells. Partners found that the presence of SAMHD1 in myeloid cells allows HIV-1 to escape from immune recognition. They have also demonstrated that neutralising antibodies can prevent cell-to-cell transmission of HIV in patients under therapy. As a result, reversal of HIV latency requires activation of cellular factors implicated in viral transcription or inflammation. To further validate these antiretroviral strategies the consortium is in the process of developing a novel primate animal model that perfectly mimics HIV infection.

Taken together, the activities of HIT HIDDEN HIV pursue a highly innovative approach in eradicating HIV. They aim to confront the infection by awakening the immune system to 'see' and kill the persisting viral reservoir. Given the high cost and difficulty of sustaining existing treatments, a short-term anti-HIV regimen is a more feasible approach, especially for developing countries.