HIV-1 Infection Triggers Hematopoietic Suppression and Multilineage cytopenia through IFN-gamma Signaling

Various hematological abnormalities, including anemia, thrombocytopenia, neutropenia, and leukopenia, are common in people with HIV-1, indicating interference with multipotent hematopoietic progenitor cells. The hematopoietic dysfunction triggered during HIV-1 infection remains unclear because this process is difficult to model in vitro due to the complexity of the bone marrow niche. Here, we utilized humanized mouse models to dissect the molecular and cellular mechanisms driving multilineage cytopenia during HIV-1 infection. We demonstrated that viral infection triggered bone marrow failure through activation and subsequent loss of multipotency of human hematopoietic stem cells. Using a unique bone marrow chimeric system, we found that ablation of IFN-gamma signaling restored the functionality of HSPCs. Furthermore, HIV-1 infection led to infiltration of IFN-gamma producing CD8+ T cells into the bone marrow niche, and depletion of these cells alleviate the hematopoietic suppression. These findings reveal the hematopoietic response during HIV-1 infection and implicate IFN-gamma as a driver of bone marrow failure.