title: HIV-1 negatively affects the survival/maturation of cord blood CD34(+) hematopoietic progenitor cells differentiated towards megakaryocytic lineage by HIV-1 gp120/CD4 membrane interaction.
abstract: To investigate the mechanisms involved in the human immunodeficiency virus type 1 (HIV-1)-related thrombocytopenia (TP), human umbilical cord blood (UCB) CD34(+) hematopoietic progenitor cells (HPCs) were challenged with HIV-1(IIIb) and then differentiated by thrombopoietin (TPO) towards megakaryocytic lineage. This study showed that HIV-1, heat-inactivated HIV-1, and HIV-1 recombinant gp120 (rgp120) activated apoptotic process of megakaryocyte (MK) progenitors/precursors and decreased higher ploidy MK cell fraction. All these inhibitory effects on MK survival/maturation and platelets formation were elicited by the interaction between gp120 and CD4 receptor on the cell membrane in the absence of HIV-1 productive infection. In fact, in our experimental conditions, HPCs were resistant to HIV-1 infection and no detectable productive infection was observed. We also evaluated whether the expression of specific cytokines, such as TGF-beta1 and APRIL, involved in the regulation of HPCs and MKs proliferation, was modulated by HIV-1. The specific protein and mRNA detection analysis, during TPO-induced differentiation, demonstrated that HIV-1 upregulates TGF-beta1 and downregulates APRIL expression through the CD4 engagement by gp120. Altogether, these data suggest that survival/differentiation of HPCs committed to MK lineage is negatively affected by HIV-1 gp120/CD4 interaction. This long-term inhibitory effect is also correlated to specific cytokines regulation and it may represent an additional mechanism to explain the TP occurring in HIV-1 patients.
authors.affiliation: Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Bologna, Italy. davide.gibellini@unibo.it
authors.forename: Davide
authors.initials: D
authors.lastname: Gibellini
authors.forename: Francesca
authors.initials: F
authors.lastname: Vitone
authors.forename: Marina
authors.initials: M
authors.lastname: Buzzi
authors.forename: Pasqua
authors.initials: P
authors.lastname: Schiavone
authors.forename: Elisa
authors.initials: E
authors.lastname: De Crignis
authors.forename: Ronny
authors.initials: R
authors.lastname: Cicola
authors.forename: Roberto
authors.initials: R
authors.lastname: Conte
authors.forename: Cristina
authors.initials: C
authors.lastname: Ponti
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Re
mesh_terms: D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D025461:Feedback, Physiological / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism*; D015658:HIV Infections / Q000150:complications* / Q000276:immunology / Q000503:physiopathology; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007231:Infant, Newborn; D008533:Megakaryocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D013921:Thrombocytopenia / Q000378:metabolism / Q000503:physiopathology / Q000821:virology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D053773:Transforming Growth Factor beta1; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13