Abstract
ABSTRACTHuman immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) infection causes myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD14+ CD16+) through largely unknown cellular and molecular pathways. The mouse cells thought to be equivalent to human CD14+ CD16+ cells are CD11b+ Gr1+ myeloid-derived suppressor cells (MDSC). We used HIV transgenic (Tg) mouse models to study MDSC, namely, CD4C/Nef Tg mice expressing nef in dendritic cells (DC), pDC, CD4+ T, and other mature and immature myeloid cells and CD11c/Nef Tg mice with a more restricted expression, mainly in DC and pDC. Both Tg strains showed expansion of granulocytic and CD11b+ Gr1low/int cells with MDSC characteristics. Fetal liver cell transplantation revealed that this expansion was stroma-independent and abrogated in mixed Tg/non-Tg 50% chimera. Tg bone marrow (BM) erythroid progenitors were decreased and myeloid precursors increased, suggesting an aberrant differentiation likely driving CD11b+ Gr1+ cell expansion, apparently cell autonomously in CD4C/Nef Tg mice and likely through a bystander effect in CD11c/Nef Tg mice. Hck was activated in Tg spleen, and Nef-mediated CD11b+ Gr1+ cell expansion was abrogated in Hck/Lyn-deficient Nef Tg mice, indicating a requirement of Hck/Lyn for this Nef function. IL-17 and granulocyte colony-stimulating factor (G-CSF) were elevated in Nef Tg mice. Increased G-CSF levels were normalized in Tg mice treated with anti-IL-17 antibodies. Therefore, Nef expression in myeloid precursors causes severe BM failure, apparently cell autonomously. More cell-restricted expression of Nef in DC and pDC appears sufficient to induce BM differentiation impairment, granulopoiesis, and expansion of MDSC at the expense of erythroid maturation, with IL-17→G-CSF as one likely bystander contributor.IMPORTANCE HIV-1 and SIV infection often lead to myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD14+ CD16+), with the latter likely involved in neuroAIDS. We found that some transgenic (Tg) mouse models of AIDS also develop accumulation of mature and immature cells of the granulocytic lineage, decreased erythroid precursors, and expansion of MDSC (equivalent to human CD14+ CD16+ cells). We identified Nef as being responsible for these phenotypes, and its expression in mouse DC appears sufficient for their development through a bystander mechanism. Nef expression in myeloid progenitors may also favor myeloid cell expansion, likely in a cell-autonomous way. Hck/Lyn is required for the Nef-mediated accumulation of myeloid cells. Finally, we identified G-CSF under the control of IL-17 as one bystander mediator of MDSC expansion. Our findings provide a framework to determine whether the Nef>Hck/Lyn>IL-17>G-CSF pathway is involved in human AIDS and whether it represents a valid therapeutic target.
Highlights
IMPORTANCE Human immunodeficiency virus (HIV)-1 and simian immunodeficiency virus (SIV) infection often lead to myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD141 CD161), with the latter likely involved in neuroAIDS
To determine whether similar accumulation of CD11b1 Gr11 cells would be observed in Tg mice expressing Nef in the same cells as those expressing CD4 in humans, we studied the CD4C/Nef Tg mice that express Nef under the regulatory elements of the human CD4 gene [14]
Because Nef has been reported to bind to members of the Src family, in particular to Hck [32], and to activate them [33], we studied the involvement of these signaling molecules in the expansion of CD11b1 Gr11 cells
Summary
IMPORTANCE HIV-1 and SIV infection often lead to myelodysplasia, anemia, and accumulation of inflammatory monocytes (CD141 CD161), with the latter likely involved in neuroAIDS. MDSC are immature, heterogeneous (CD11b1 Gr1low, CD11b1 Gr1int, and CD11b1 Gr1high) [5], and likely originate from myeloid granulocytic/macrophage progenitors (GMP) [4] Conditions favoring their expansion are associated with accumulation of myeloid precursors, as documented in mice deficient for SHIP [6] or Lyn/Hck [7] genes. These Tg mice express only Nef with the regulatory elements of the human CD4 gene (CD4C) in the same cells as those infected with HIV in human, i.e., in CD41 T cells and myeloid cells, and develop an AIDS-like disease [14] They show abnormalities within two distinct Tg myeloid cell subsets: an enhanced production of ferritin by macrophages [15] and an accumulation of immature CD11c1 CD11bhi DC in spleen [16]. We report that Nef, expressed in these Tg mice, induces the accumulation of other cell subsets, the CD11b1 Gr11 cells, some belonging to the granulocytic lineage and others showing MDSC characteristics
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