Skip to main content

Accelerating HIV Cure in Europe

Deliverables

New CTIP2-associated complexes; Validate newly identified proteins/ncRNA ; The association of CTIP2 expression and chronic inflammation of HIV-1 treated patients; Test and select drugs to be validated in WP5

Characterise CTIP2-associated complexes by gel filtration/immunoprecipitations combined with mass spectrometry (protein content) and high throughput sequencing (non coding RNA). Validate newly identified proteins/ncRNA by lost-/gain-of-function studies using in vitro HIV-1 latency cellular models. Define the impact of the HIV-1 cART on the presence of CTIP2 (and its associated complexes), in CD4+ T cells and monocytes from HIV-1 patients (MMUH cohorts) Study of the correlation between CTIP2-level and CTIP2-associated complexes with the inflammatory status of HIV-1 patients (MMUH cohorts). Test and select new latency-reversible compounds targeting functionally validated CTIP2-associated proteins using in vitro latency models.

Validation of new identified therapeutic agent or class of agents identified in WP4

Examine the potency of new compounds selected in WP4 using ex vivo reactivation studies on CD4 T cells reservoirs of HIV-1 infected patients on suppressive cART. Examine the cytotoxicity and T cell activation affect in primary PBMCs over periods of 24-72h, for new compounds to be tested in ex vivo latency assays.

OUTREACH Project 2

OUTREACH ACTIVITY 2 This outreach event will be coordinated by NUID UCD and ESRs from our consortium will be in charge of running this outreach programme in their respective organisation. Public: Students in each University campus of the consortium. Event:On World AIDS day, taking place every year December 1st, we will run the campaign “Student know you status”. Delivery: Activities targeted at students including seminars, information stands, movies projections will address believes, attitudes and concerns associated with HIV/AIDS. Furthermore, a European debating competition hosted by NUID UCD Medical Society will take place in NUID UCD debating Chamber and will be share with other universities via live webcast.

Histone methylation and DNAm profiles of the HIV-1 promoter ; new druggable targets within HMTs, HDMs and DNMTs; Test and select drugs to be validated in WP5

Compare the histone methylation status of the HIV promoter following siRNA-mediated depletion of HMTs or HDMs using in vitro HIV-1 latency cellular models. Compare the HIV promoter DNA methylation status by the bisulfite conversion sequencing following DNMTs depletion using in vitro HIV-1 latency cellular models. Compare the HIV promoter methylation status in distinct memory CD4+ T cells subsets latently infected with HIV in patient under suppressive cART. Analyze HMTs/HDMs recruitment at the HIV-1 promoter in vivoby chromatin immunoprecipitation (ChIP)-qPCR using in vitro HIV-1 latency cellular models. Compare HIV-1 proviral gene expression and production following siRNA-mediated DNMTs knockdown using in vitro HIV-1 latency cellular models. Test and select new latency-reversible compounds targeting functionally validated HMTs, HDMs or DNMTs using in vitro HIV-1 latency cellular models.

Identification of determinants responsible for the patient-specific variations in response to LRA

Analyze the effect of the HIV-1 inducers on viral reactivation in ex vivo cultures of CD8+-depleted PBMCs from different cluster of patient as follow: cART started early during the primary infection versus during the chronic phase, and sub-separated into low and high proviral load.

Role of T cell metabolic pathways in the regulation of HIV latency/reactivation; Role of the SUMO pathway in the regulation of HIV latency/reactivation; Select drugs to be validated in WP5

Perform dose-response analysis and combinatorial studies for reactivation of HIV-1 gene expression using pharmacological compounds targeting T cell metabolic junction, and in vitro HIV-1 latency cellular models. Examine the role of SUMO effectors by lost-/gain-of-function studies using in vitro HIV-1 latency cellular models. Perform dose-response analysis and combinatorial studies for reactivation of HIV-1 gene expression using pharmacological compounds targeting selected SUMO pathway effectors using in vitro HIV latency models.

Mode of action of MATR3, PTB, PSF and HIV reactivation; Discovery of new host factors implicated in HIV-1 RNA nuclear export and HIV-1 post-transcriptional silencing; Select drugs to be validated in WP5

Define the mode of action of MATR3, PTB, PSF on HIV RNA nuclear export. Exploiting shRNA and CRISPR/Cas9 systems we will explore MATR3 mutants and assess their behaviour by functional assays including monitoring of HIV RNA nuclear export by live imaging. Live imaging will be complemented by studies at NUID UCD. Develop an unbiased high-throughput assay for the identification of other potential post-transcriptional blocks of HIV reactivation, which include nuclear export of HIV RNA, translation and packaging. Test and select new latency-reversible compounds targeting functionally host proteins involved in post-transcriptional HIV-1 silencing using in vitro latency models.

Publication of research reports and articles in high-impact peer-reviewed journals

One fundamental goal will be to disseminate our research findings to the scientific and medical community via research reports and articles in high-impact peer-reviewed journals including but not limited to Journals with a focus on clinical infectious diseases covering areas as the treatment and research of HIV/AIDS (Lancet infectious diseases, Clinical Infectious Diseases, AIDS, Retrovirology), on translational medicine (Journal of experimental medicine, PLOS Medicine, Science translational Medicine) or on viral-host interface (Cell Host Microbes, Plos Pathogens). Furthermore, at equivalent impact factor, priority will be given to Open Access peer reviewed journals in order to increase the visibility of our work and encouraging open discourse

Determination of the potency, synergistic activity and toxicity of novel classes of LRA

HMTI, HDACI, HDMT inhibitors, DNA methylation inhibitors, NF-ĸB inducers and compounds releasing active P-TEFb complex will be tested first alone and in combination in latently-infected cell lines. Analyze the effect of the HIV-1 inducers on viral reactivation in ex vivo cultures of CD8+-depleted PBMCs. We will also study the patient-specific variations in the ex vivo reactivation capacity of the HIV-infected cells in ex vivo cultures of resting CD4+ T cells. Resting (CD69- CD25- HLA-DR-)

Develop Website, LinkedIn, Newsletter

Our research and collaborative activities towards an HIV Cure will be relayed by the following communication tools: • Website Targeted Audience: Scientific, medical and public health communities and General Public Access: Open Objective: To provide information in an easy-to-understand format about our consortium structure and members, our aim and our collaborative activities with an emphasis on the collaborative nature of our working relationship. The website will include members profiles describing their expertise and facilities. A glossery of terminology, Infographics, illustrations and reading list will be provided on the website to facilate the understanding of our website content. • Facebook with Event calendar Targeted Audience: Scientific, medical and public health communities and General Public Access: Open Objective: This flexible social media platform will allow for prompt updates on EU4HIVCURE consortium activities and outputs with an emphasis on research collaboration and outcomes, secondeme

Validation of new identified therapeutic agent or class of agents identified in WP2

Examine the potency of new compounds selected in WP2 using ex vivo reactivation studies on CD4 T cells reservoirs of HIV-1 infected patients on suppressive cART Examine the cytotoxicity and T cell activation affect in primary PBMCs over periods of 24-72h, for new compounds to be tested in ex vivo latency assays.

Research presentation/semminars at international conferences

We will present our work to conferences and workshops dedicated to understanding the mechanisms of HIV-1 persistence and finding a HIV cure. These include -taking place every two years- the International Workshop on HIV Persistence during Therapy (Miami); the IAS Conference on HIV Pathogenesis, Treatment and Prevention”; Frontiers of Retrovirology the Keystone symposia: “HIV Persistence: Pathogenesis and Eradication” California, USA; the CHSL « Retroviruses »; and the Keystone symposia: HIV Persistence: Pathogenesis and Eradication; the International Conference on HIV and AIDS. Sharing our results and outcomes through these pathways will help drive strengthen the impact drive forward the effort towards the development of an AIDS/ HIV cure

Validation of new identified therapeutic agent or class of agents identified in WP3

Examine the potency of new compounds selected in WP3 using ex vivo reactivation studies on CD4 T cells reservoirs of HIV-1 infected patients on suppressive cART. Examine the cytotoxicity and T cell activation affect in primary PBMCs over periods of 24-72h, for new compounds to be tested in ex vivo latency assays.

OUTREACH Project 1

OUTREACH ACTIVITY 1 This outreach event will be coordinated by NUID UCD, and ESRs from our consortium will be in charge of running this outreach programme in their respective organisation. Public: Secondary school 15-year-old pupils from socio-economic disadvantaged backgrounds associated with low progression to third level education. Countries: France, Belgium, Italy and Ireland. Event: 1 day event, in October/November taking place simultaneously in different EU Partners countries once a year, for four years. Delivery: o One week prior our event, participants will answer questionnaire about HIV/AIDS-related issues. o On the day (morning), following a brief Skype session to introduce pupils from each country, classes and their teachers will meet with professional (consultant, nurse, researcher) and HIV positive individuals and patients advocates in question/answer sessions to facilitate their understanding of this infectious disease, its transmission, current treatments efficacity and limitations, and the na

Establish thematic Workshops

We will exploit workshops as a tool to transfer of knowledge and know-how of our consortium core research disciplinary skills and expertise. These will be organized during the month of July every year as consortium members will have less commitments. These four-days workshops and their associated themes are listed below • Dissecting the Host-virus interface with system-wide screening approach. Month 8, NUID UCD, Dublin, Ireland. • State of the Art tools for HIV Cure Research. Month 20, Saint Pierre Hospital, Brussels, Belgium. • Epigenetic control of HIV post-integration latency. Month 32, University of Strasbourg, France. Speakers from the consortium will provide expert overviews of their fields, followed by in-depth discussions of their own work. Importantly, secondees will be invited to share their acquired knowledge and experience, with a critical view, as they will beneficiate from expertise from their home-institution and the newly acquired ones. ESR and ER will be invited to submit abstracts an

Implementation of Secondments across the EU4HIVCURE consortium

The embedded nature of our secondments , which are at the core of our collaborative strategy, will enable us to go beyond the simple association of a clinician with a biomedical researcher. Indeed, the role of the secondee is not only to learn and implement a given technique or experimental approach but to act as the catalyst of the collaboration. Implementation: In order to ensure that the quality of knowledge sharing is maintained at the highest possible level, a number of specific measures will be undertaken: Explicit agreements will be drawn in advance of the secondments, to document the learning and research objectives, to highlight the interdependence, joint ownership, and collective responsibility for the secondment and research project. In addition they will include publication authorships, IPs, Patents and/or non-disclosure agreements. Principal Ivestigators (PI’s) from all consortium members are committed to provide an environment favorable to knowledge transfer and to maximise the outputs of the

Close-out meeting

Close-out Meeting, organised by ICGEB will take at M46 place in their facility in Trieste, Italy. During our final meeting hosted by ICGEB in Italy, time will be allocated to produce video seminars given by our EU4HIVCURE consortium members on HIV CURE Research. We will benefits from ICGEB facilities to record and edit these video seminars, which will be broadcasted using ICGEB’s own channel on iTunesU.

Searching for OpenAIRE data...

Publications

Targeting the Brain Reservoirs: Toward an HIV Cure

Author(s): Céline Marban, Faezeh Forouzanfar, Amina Ait-Ammar, Faiza Fahmi, Hala El Mekdad, Fadoua Daouad, Olivier Rohr, Christian Schwartz
Published in: Frontiers in Immunology, Issue 7, 2016, ISSN 1664-3224
DOI: 10.3389/fimmu.2016.00397

On the way to find a cure: Purging latent HIV-1 reservoirs

Author(s): Christian Schwartz, Sophie Bouchat, Céline Marban, Virginie Gautier, Carine Van Lint, Olivier Rohr, Valentin Le Douce
Published in: Biochemical Pharmacology, Issue 146, 2017, Page(s) 10-22, ISSN 0006-2952
DOI: 10.1016/j.bcp.2017.07.001

Improving combination antiretroviral therapy by targeting HIV-1 gene transcription

Author(s): Valentin Le Douce, Amina Ait-Amar, Faezeh Forouzan far, Faiza Fahmi, Jose Quiel, Hala El Mekdad, Fadoua Daouad, Céline Marban, Olivier Rohr, Christian Schwartz
Published in: Expert Opinion on Therapeutic Targets, Issue 20/11, 2016, Page(s) 1311-1324, ISSN 1472-8222
DOI: 10.1080/14728222.2016.1198777

HIC1 controls cellular- and HIV-1- gene transcription via interactions with CTIP2 and HMGA1

Author(s): Valentin Le Douce, Faezeh Forouzanfar, Sebastian Eilebrecht, Benoit Van Driessche, Amina Ait-Ammar, Roxane Verdikt, Yoshihito Kurashige, Céline Marban, Virginie Gautier, Ermanno Candolfi, Arndt G. Benecke, Carine Van Lint, Olivier Rohr, Christian Schwartz
Published in: Scientific Reports, Issue 6/1, 2016, ISSN 2045-2322
DOI: 10.1038/srep34920

The Relevance of Post-Transcriptional Mechanisms in HIV Latency Reversal

Author(s): Ambra Sarracino, Alessandro Marcello
Published in: Current Pharmaceutical Design, Issue 23/28, 2017, ISSN 1381-6128
DOI: 10.2174/1381612823666170803102355

Posttranscriptional Regulation of HIV-1 Gene Expression during Replication and Reactivation from Latency by Nuclear Matrix Protein MATR3

Author(s): Ambra Sarracino, Lavina Gharu, Anna Kula, Alexander O. Pasternak, Veronique Avettand-Fenoel, Christine Rouzioux, Maryana Bardina, Stéphane De Wit, Monsef Benkirane, Ben Berkhout, Carine Van Lint, Alessandro Marcello
Published in: mBio, Issue 9/6, 2018, ISSN 2150-7511
DOI: 10.1128/mbio.02158-18

HIV-1 Vpr mediates the depletion of the cellular repressor CTIP2 to counteract viral gene silencing

Author(s): F. Forouzanfar, S. Ali, C. Wallet, M. De Rovere, C. Ducloy, H. El Mekdad, M. El Maassarani, A. Aït-Ammar, J. Van Assche, E. Boutant, F. Daouad, F. Margottin-Goguet, C. Moog, C. Van Lint, C. Schwartz, O. Rohr
Published in: Scientific Reports, Issue 9/1, 2019, ISSN 2045-2322
DOI: 10.1038/s41598-019-48689-x

Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs

Author(s): Amina Ait-Ammar, Anna Kula, Gilles Darcis, Roxane Verdikt, Stephane De Wit, Virginie Gautier, Patrick W. G. Mallon, Alessandro Marcello, Olivier Rohr, Carine Van Lint
Published in: Frontiers in Microbiology, Issue 10, 2020, ISSN 1664-302X
DOI: 10.3389/fmicb.2019.03060

CD32+CD4+ T Cells Are Highly Enriched for HIV DNA and Can Support Transcriptional Latency

Author(s): Gilles Darcis, Neeltje A. Kootstra, Berend Hooibrink, Thijs van Montfort, Irma Maurer, Kevin Groen, Suzanne Jurriaans, Margreet Bakker, Carine van Lint, Ben Berkhout, Alexander O. Pasternak
Published in: Cell Reports, Issue 30/7, 2020, Page(s) 2284-2296.e3, ISSN 2211-1247
DOI: 10.1016/j.celrep.2020.01.071

Microglial Cells: The Main HIV-1 Reservoir in the Brain

Author(s): Clementine Wallet, Marco De Rovere, Jeanne Van Assche, Fadoua Daouad, Stéphane De Wit, Virginie Gautier, Patrick W. G. Mallon, Alessandro Marcello, Carine Van Lint, Olivier Rohr, Christian Schwartz
Published in: Frontiers in Cellular and Infection Microbiology, Issue 9, 2019, ISSN 2235-2988
DOI: 10.3389/fcimb.2019.00362

The Molecular Biology of HIV Latency

Author(s): Georges Khoury, Gilles Darcis, Michelle Y. Lee, Sophie Bouchat, Benoit Van Driessche, Damian F. J. Purcell, Carine Van Lint
Published in: HIV Vaccines and Cure - The Path Towards Finding an Effective Cure and Vaccine, Issue 1075, 2018, Page(s) 187-212
DOI: 10.1007/978-981-13-0484-2_8

Molecular Control of HIV and SIV Latency

Author(s): Gilles Darcis, Benoit Van Driessche, Sophie Bouchat, Frank Kirchhoff, Carine Van Lint
Published in: HIV-1 Latency, Issue 417, 2018, Page(s) 1-22
DOI: 10.1007/82_2017_74