Periodic Reporting for period 2 - EU4HIVCURE (Accelerating HIV Cure in Europe)
Período documentado: 2018-02-01 hasta 2020-01-31
Finding a CURE for 37 Million individuals living with HIV/AIDS is one of the great global health challenges of the 21st century. The major obstacle to HIV eradication in patients under combination Anti-Retroviral therapy (cART) is the persistence of latent HIV cellular reservoirs, where the integrated viral genome is transcriptionally silenced but replication competent, and can escape both cART and immune response.
Current strategies towards an HIV CURE aim at purging persistent latent reservoirs by forcing viral gene expression using epigenetic-modifying agents, including Histone Deacetylase inhibitors (HDACi) while maintaining patients on efficient cART. Once viral gene expression and viral particle production is reignited, the viral reservoirs are once again visible and can be targeted and eliminated by the immune system with the help of immune bosting strategies. However, in clinical trials, epigenetic inhibitors including SAHA, when used as single agents, have shown modest impact in inducing efficient HIV gene expression and/or virion production. Furthermore, there was no impact on the latent reservoir size in vivo. These studies highlight that additional layers of control for HIV gene silencing limit the impact of current LRA-based strategies and that these blocks need to be collectively unlocked if we want to effectively force HIV gene expression and viral production.
To investigate novel avenues of research towards an HIV cure, it is critical to expand the repertoire of novel targetable proteins and to develop new classes of Latency Reversing Agents (LRAs) and combination of thereof, to be included as part new “Shock and Kill” strategies. In this context and driven by our common engagement in accelerating HIV CURE research in Europe, we have developed the EU4HIVCURE consortium, which is built upon dynamic collaborations between academic researchers and Infectious Diseases clinicians in Europe and was awarded the Horizon 2020 MSCA-RISE-2015 funding award from the European Commission.
Current strategies towards an HIV CURE aim at purging persistent latent reservoirs by forcing viral gene expression using epigenetic-modifying agents, including Histone Deacetylase inhibitors (HDACi) while maintaining patients on efficient cART. Once viral gene expression and viral particle production is reignited, the viral reservoirs are once again visible and can be targeted and eliminated by the immune system with the help of immune bosting strategies. However, in clinical trials, epigenetic inhibitors including SAHA, when used as single agents, have shown modest impact in inducing efficient HIV gene expression and/or virion production. Furthermore, there was no impact on the latent reservoir size in vivo. These studies highlight that additional layers of control for HIV gene silencing limit the impact of current LRA-based strategies and that these blocks need to be collectively unlocked if we want to effectively force HIV gene expression and viral production.
To investigate novel avenues of research towards an HIV cure, it is critical to expand the repertoire of novel targetable proteins and to develop new classes of Latency Reversing Agents (LRAs) and combination of thereof, to be included as part new “Shock and Kill” strategies. In this context and driven by our common engagement in accelerating HIV CURE research in Europe, we have developed the EU4HIVCURE consortium, which is built upon dynamic collaborations between academic researchers and Infectious Diseases clinicians in Europe and was awarded the Horizon 2020 MSCA-RISE-2015 funding award from the European Commission.
Over the first 24 months of our four years programme, we have capitalized on this strategic investment and successfully developed and implemented a molecular pathway-driven translational research platform (Figure 1), which merges our demonstrated strengths and expertise in molecular virology, proteomic and genomic screening, primary and patients-cell based assays, targeted drug screening, established patient cohorts, clinical management trials, and clinical practice. Importantly, this collaborative platform is operational and dedicated to host and facilitate our scientific agenda which is to translate the identification of alternative targets for therapeutic intervention into concrete new classes of latency-reversing drugs, as part of the development of an HIV CURE.
Our aim is to dissect the intricate mechanisms controlling HIV-1 latency and identify new druggable targets to develop novel latency-reversing strategies and eradicate persistent viral reservoirs by forcing HIV-1 gene expression.