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.