Grant: Project Grant

The discovery of human immunodeficiency virus type 1 (HIV-1) in 1983 was followed by major advances in understanding disease pathogenesis and the elucidation of the viral replication cycle at the molecular level. This knowledge allowed the design of the antiretroviral therapy (ART) that efficiently controls viral replication at undetectable plasma levels, thus robustly reducing the risk of transmission and transforming the deadly epidemic into a manageable chronic disease. Despite these advances, HIV-1 infection remains a significant health issue at the international level. The major barrier to HIV-1 cure is the persistence of viral reservoirs (VRs) in long-lived immune cells, therefore requiring life-long treatment in people living with HIV (PLWH). ART does not interfere with the transcription step of the viral replication cycle, therefore allowing residual HIV transcription in activated VRs, a major cause of non-AIDS co-morbidities in PLWH. Conversely, the transcriptional HIV latency contributes to the escape of quiescent VRs from the clearance by the immune system. Therefore, understanding molecular mechanisms of HIV transcription/latency is key for HIV remission/eradication. Most recently, our studies focused on the identification of host cell transcription factors that regulate HIV replication, mainly in CD4+ T cells enriched in HIV reservoirs in ART-treated PLWH. Among such transcription factors, we recently identified the aryl hydrocarbon receptor (AhR) as a new barrier to HIV replication and outgrowth in CD4+ T cells. This Project Grant Application relies on a team of applicants/collaborators with internationally renowned expertise in Immunology, Virology, and pre-clinical animal testing. Our goals is to uncover the mechanisms of action of AhR in immune cells targeted by HIV-1 for infection/persistence and to provide a proof-of-concept that pharmacological AhR targeting of VRs may represent an important therapeutic venue in HIV remission/cure research.