Induced cell death and/or induced cell killing for HIV Cure
This proposal establishes a new research infrastructure between the Erasmus MC HIV Eradication Group (EHEG) University Medical Center Utrecht (UMCU) and private partners, ViiV and First Health Pharmaceuticals (FHP), for the identification and elimination of the HIV latent reservoir. HIV Cure seeks ways to identify, manipulate, and eradicate the latent reservoir. “Shock and kill” strategies require activating HIV gene expression in latently infected cells by latency reversal agents (LRAs).
Almost 38 million people live with chronic HIV infection and only life-long treatment (cART), prevents them from progression to AIDS and death. Given the large numbers it is difficult to reach the current goals of 90-90-90 (90% HIV status known, 90% on treatment and 90% undetectable plasma HIV RNA). In addition, a latent HIV reservoir persists. This reservoir provokes a viral rebound upon cessation of treatment. Elimination of the reservoir is therefore a prerequisite for HIV cure.
One of the project goals is to find new LRA’s or LRA combinations that activate latent provirus, without unwanted cellular activation. Cells that start actively producing virus or viral products need to be eliminated, either via immune responses against HIV-infected cells. A more innovative approach to eliminate LRA-induced HIV infected cells emerging out of latency is to pharmacologically target danger sensing, stress and apoptotic pathways in order to induce cell death (ICD) in reactivated HIV expressing cell.
New assays to reliably quantify the HIV latent reservoir and the effects of LRA and shock and kill strategies will be developed. Novel LRA’s will be tested as well as alternative strategies to induce and kill the reservoir. This will help to develop and test innovative combination LRA-ICD strategies in innovative ex vivo models for cure potential, and translate findings to a unique clinical cohort of in-depth characterised HIV infected patients.