Since its discovery in the early 80s, the human immunodeficiency virus (HIV) has spread around the world with remarkable speed making nearly 30 million of deaths. The outcome of HIV infection has markedly improved over the past decade owing to significant progresses accomplished in drug development. Nowadays, HIV-infected individuals treated with antiretroviral therapy (ART) can achieve and sustain durable viral suppression and systemic immune reconstitution. Nevertheless, despite these successes, current drugs still fail to eradicate the virus and to fully restore normal health. Long-term treated patients show chronic hyper immune activation and inflammation and are consequently at higher risk of developing non-AIDS-related complications including cardiovascular, bone and neurocognitive diseases as well as malignancies. Independently of viral replication, levels of immune activation predict disease progression and mortality in ART-treated individuals. Over the past five years, the gut and its associated lymphoid tissue (GALT) have emerged as key contributors of HIV pathogenesis. The GALT is a substantial viral reservoir and several lines of evidence indicate that chronic immune activation observed in long-term treated patients is related to persistent low-level of HIV replication in the gut, alterations in the intestinal mucosal immune system, epithelial breakdown and translocation of bacterial antigens. While these processes have been observed during the acute and chronic phase of HIV and SIV infection, their successions as well as the precise molecular mechanisms that connect them require further exploration. It is also poorly known whether starting ART at an early stage of infection may influence the onset and progression of these mechanisms and reduce immune activation. Research on the early phase of HIV-infection has long been hampered by the limited availability of samples from acutely infected persons and the lack of animal model that mirrors all of the striking characteristics of human-infection. In this regard, the development of new generations of humanized mice models supporting and mimicking HIV transmission and pathogenesis seems to be an invaluable tool. We propose in the current project (modified form of the CORE preproposal submitted by V. Fievez in 2013), to explore the early mechanisms of immune activation in the gut and to decipher the impact of ART on these processes by using and optimizing a humanized mice model recently developed in Pr. M. Moutschen laboratory (Department of Infectious Diseases, ULG, Belgium). We seek to decipher (i) the intricate interplay between epithelial and immune cells during the acute phase of HIV infection and their effects on the intestinal barrier integrity and microbial translocation (ii) the dynamic of HIV pathogenesis and the dissemination of the virus in the gut (iii) the role of ART on the early mechanisms of immune dysfunction and activation in the gut (iv) the peripheral and intestinal cellular source of viral reservoirs that contain transcriptionally competent latent viruses. Absolute quantification of all HIV viral DNA forms and unspliced RNA contained in the cellular reservoirs of the gut will be performed by a droplet digital PCR technique recently developed in Pr. L. Vandekerckhove laboratory (HIV Translational Research Unit, University of Ghent, Belgium).Determination of the onset of immune activation in the absence and in the presence of ART and their consequences for HIV persistence will foster the design of novel therapeutic strategies aiming to reduce mortality and morbidity in ART-treated patients. In addition, the humanized mice model is an invaluable tool for studying human cells in a physiological 3D complex environment and its implementation in Luxembourg represents therefore an asset for the strategic development of the Laboratory of Retrovirology (LRTV), CRP-santé and other Luxembourgish research institutions.