Background
HIV-1 infection commonly causes multiple hematopoietic abnormalities, known as pancytopenia, including lymphopenia, anemia, granulocytopenia, and thrombocytopenia, suggesting a central deficiency in bone marrow hematopoiesis. However, the mechanism by which HIV-1 infection leads to bone marrow hematopoietic defects remains unknown due to the lack of appropriate in vivo models. In this study, we established a humanized mouse model that successfully recapitulates the bone marrow cytopenia observed in people living with HIV (PLWH).
Methods
Newborn mice were transplanted with human cord blood-derived CD34+ cells. Mice were infected with HIV-1 9-10 weeks post-transplantation when sufficient levels of human CD45+ (huCD45+) cells were confirmed. Different R5-tropic strains (HIVBaL, HIVYU2, HIVJR-CSF, and transmitted virus HIVRejo) were utilized for HIV-1 infection. The changes of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow were analyzed using flow cytometry, RNA-seq, and scRNA-seq e.t.c.
Results
Post 3-4 weeks of infection, HIV-1 infected mice showed a dramatic reduction in both the percentage and count of huCD45+, CD34+, and Lin–CD34+ cells in the bone marrow compared to uninfected controls. ScRNA-seq analysis of bone marrow CD34+ cells revealed that both lymphoid and myeloid progenitors were reduced, and myeloid progenitors had a more significant decrease. Using colony-forming unit assay and secondary transplantation, we demonstrated that bone marrow hematopoietic stem cells isolated from HIV-1 infected mice had reduced stemness and differentiation potency compared to uninfected controls. Since increased response to the IFNγ signaling was observed in myeloid progenitor cells via RNA-seq and scRNA-seq, we generated IFNγ receptor knocked out humanized mice. In these mice, hematopoietic suppression by HIV-1 infection was rescued, further supporting the role of IFNγ in HSPC suppression. Additionally, we identified activated CD8+ T cells as the primary source of IFNγ. Finally, IFNγ was found to trigger rapid HSPC proliferation, leading to the exhaustion of the HSPC pool over time.
Conclusions
Using this humanized model, we identified IFNγ signaling as a key factor in driving bone marrow failure post-acute HIV infection. Importantly, blocking IFNγ signaling rescued HSPC defects, thereby protecting the hematopoietic system during the early stages of infection. These findings offer valuable insights into the clinical management and treatment of PLWH.
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