Subject(s)
Antigens, CD34/immunology , Gene Products, nef/physiology , PPAR gamma/physiology , Simian Acquired Immunodeficiency Syndrome/physiopathology , Animals , Gene Expression Regulation , Macaca , STAT5 Transcription Factor/genetics , Simian Acquired Immunodeficiency Syndrome/genetics , Simian Acquired Immunodeficiency Syndrome/immunologyABSTRACT
Infection of primates by HIV-1 and SIV induces multiple hematological abnormalities of central hematopoietic origin. Although these defects greatly contribute to the pathophysiology of HIV-1 infection, the molecular basis for altered BM function remains unknown. Here we show that when cynomolgus macaques were infected with SIV, the multipotent potential of their hematopoietic progenitor cells was lost, and this correlated with downregulation of STAT5A and STAT5B expression. However, forced expression of STAT5B entirely rescued the multipotent potential of the hematopoietic progenitor cells. In addition, an accessory viral protein required for efficient SIV and HIV replication and pathogenicity, "Negative factor" (Nef), was essential for SIV-mediated impairment of the multipotent potential of hematopoietic progenitors ex vivo and in vivo. This newly uncovered property of Nef was both conserved between HIV-1 and SIV strains and entirely dependent upon the presence of PPARgamma in targeted cells. Further, PPARgamma agonists mimicked Nef activity by inhibiting STAT5A and STAT5B expression and hampering the functionality of hematopoietic progenitors both ex vivo and in vivo. These findings have extended the role of Nef in the pathogenicity of HIV-1 and SIV and reveal a pivotal role for the PPARgamma/STAT5 pathway in the regulation of early hematopoiesis. This study may provide a basis for investigating the potential therapeutic benefits of PPARgamma antagonists in both patients with AIDS and individuals with hematopoietic disorders.
Subject(s)
Gene Products, nef/metabolism , HIV-1/metabolism , Hematopoiesis/physiology , PPAR gamma/metabolism , STAT5 Transcription Factor/metabolism , Signal Transduction/physiology , Simian Immunodeficiency Virus/metabolism , Amino Acid Sequence , Animals , Female , Gene Products, nef/genetics , HIV-1/genetics , Hematologic Diseases/metabolism , Hematologic Diseases/physiopathology , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/physiology , Humans , K562 Cells , Macaca fascicularis , Male , Molecular Sequence Data , PPAR gamma/genetics , STAT5 Transcription Factor/genetics , Simian Immunodeficiency Virus/geneticsABSTRACT
A novel membrane protein has been identified in the course of screening for differentially expressed cDNAs in human embryonic hematopoietic sites. This 37- to 38-kDa molecule, designated KLIP-1 (killer lineage protein), consisting of 350 amino acids and containing five transmembrane domains, is encoded by the 5093-bp KLIP-1 gene, composed of nine exons and located on chromosome 6 (6p21.1-6p21.2). We found the KLIP-1 protein to be expressed by nucleated hematopoietic cells, from early embryonic hematopoietic stem cells through mature adult blood lymphoid lineages, either as membrane or as cytoplasmic molecules. In day-30/32 human embryo sections, KLIP-1 protein expression is restricted to circulating hematopoietic cells at hematopoiesis sites. Membrane KLIP-1 is expressed by fetal and adult GP-A(+) erythroblasts, the fetal liver CD34(+) subset, fetal spleen, and adult bone marrow CD56(+) NK and CD19(+) B cells. Among mature blood cells, surface KLIP-1 expression is restricted to CD56(+) NK cells, indicating KLIP-1 to be a novel marker of this population. Altogether, these results indicate that membrane export of KLIP-1 antigen is developmentally and ontogenetically regulated. The high degree of conservation of the KLIP-1 protein sequence among mammals strongly suggests that it plays an important role during hematopoiesis and may exercise similar functions in human and mouse blood cells. The KLIP-1 molecule may therefore constitute a powerful tool for improving knowledge of both human hematopoiesis and NK cell ontogeny and immune functions.
