CXCR4-associated depletion of bone marrow CD34+cells following CCR5-tropic HIV-1 infection of humanized NOD/SCID/JAK3nullmice and partial protection of those cells by a promotor-targeting shRNA

Abstract

AbstractObjectivesHematological abnormalities that include changes in bone marrow, such as in anemia and pancytopenia, are common among human immunodeficiency virus (HIV)-infected patients, particularly in the advanced stage of disease. This study aimed to provide better experimental evidence of such manifestations in animal models.DesignNOD/SCID/JAK3null(NOJ) mice were transplanted with human cord-derived CD34+cells with or without transduction with a lentiviral vector expressing a promoter-targeting shRNA called PromA.MethodsAt 16 weeks after transplantation, mice engrafted with CD34+cells were infected with CCR5-tropic HIV-1JRFL.ResultsAt week 2 post infection, HIV replication was observed in peripheral blood mononuclear cells and splenocytes. In mice transplanted with unmanipulated CD34+cells, viral replication was accompanied by a loss of peripheral/spleen CD4+CCR5+T cells. Interestingly, bone marrow CD34+cells in HIV-infected mice were also depleted, but in a CXCR4-associated manner. Conversely, the lentiviral transfer of PromA in CD34+cells prior to transplantation rendered the humanized NOJ mice resistant to HIV replication in CD4+T cells, resulting in better preservation of peripheral/spleen CD4+CCR5+T cells and bone marrow CD34+cells at two weeks after infection.ConclusionsThese results implicate the importance of evaluating hematopoietic stem/progenitor cell pools in addition to peripheral CD4+T-cell counts to assess the early stage of HIV infection. Moreover, stable gene transfer of PromA to hematopoietic stem cells not only limited HIV replication but also led to preservation of different subsets of hematopoietic cells, including bone marrow stem/progenitor cells.