Research project BL/01/SA15 (Research action BL)
Project objectives
More than 38 million people are living with HIV (PLHIV), the vast majority in Africa. While current treatments improve the overall health of patients, they fail to cure HIV-1 as the provirus integrates in the host genome of long-lived immune cells. This persistent viral reservoir causes viral rebound when treatment discontinues. Current research aims to understand (i) the molecular determinants of HIV-1 latency, (ii) the individual variability among patients and iii) novel cure strategies. Whereas the groups of Dr. Madlala and Dr. Hendrickx have been studying genetic, virological and immunological characteristics of PLHIV who are infected with subtype C, prevalent in the African PLWH, using biobanks of patient cohorts (e.g. CAPRISA, Sinikithemba), the Debyser group has been exploring how epigenetics in the chromatin environment of the provirus determine its transcriptional state. By interference with the epigenetic reader LEDGF/p75 the group develops a functional cure strategy. The collaboration between both countries opens the possibility to use the established biobanks, with subtype C strains for epigenetic characterisation and further development of the cure strategy.
Therefore, the specific objectives of the current project are to :
1. Biobank epigenetic marks of HIV-1 subtype C provirus in samples from South Africans to identify epigenetic biomarkers predicting HIV-1 reservoir size, sensitivity of the latent reservoir to LRAs and time to viral rebound;
2. Transfer of biotechnology to sequence HIV-1 provirus integration sites and epigenetic marks from KU Leuven to University of KwaZulu-Natal (UKZN) and University of Limpopo (UL).
Specific R&D cooperation
The lab at UKZN will focus on biobanking of subtype C samples from the FRESH study and the HIV Pathogenesis Programme (HPP) acute infection cohort established in Durban. These samples will be used to study the epigenetics of the provirus in HIV-1 subtype C infected patients. The Debyser lab has experience in integration site sequencing and epigenetic analysis and will therefore train postgraduate students and staff from the Madlala and Hendricks labs. This project will recruit postgraduates, masters and PhD student from the Madlala and Hendricks labs who will be trained on this biotechnology.
Added value of the network
Professor Debyser is an expert on HIV-1 integration. In 2003, his group identified LEDGFp/75 as an important cofactor for HIV-1 replication and interacting partner of HIV-1 integrase. In 2010 the group developed LEDGINs as inhibitors of the interaction integrase-LEDGF/p75 interaction. In 2016 they reported that LEDGINs retarget HIV-1 integration. Recently, they correlated HIV integration sites to epigenetic marks in the proviral chromatin environment. All studies so far were done with HIV-1 subtype B. Following postdoctoral training in the Debyser lab, Dr Madlala returned to the University of KwaZulu-Natal to establish a research group, focusing on determining the role of the HIV-1 promoter and Tat in HIV transcription and latency. Dr Hendricks has just moved from the University of KwaZulu-Natal to a previously disadvantaged university in South Africa, the University of Limpopo to establish his HIV research line molecular immunology. Within this network the relation between HIV integration sites, epigenetic marks and HIV transcription will be studied in subtype C infected African PLHIV.
Expected results
1. Biobanking of HIV-1 subtype C provirus epigenetics in South African samples.
2. Organize 2 workshops to train South African students and staff in integration site sequencing and epigenetic analysis (biotechnology) and Belgium students and staff on handling and analysis of patient samples.
3. Exchange and training of students.
4. Publish collaborative work, establish a long-term collaboration and apply for collaborative funding (e.g. Wellcome Trust, Horizon Europe, …)
5. Deposit patient samples in the HPP repository (South Africa) and plasmids and biotechnology tools in the BCCM biobank (Belgium)
