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

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‐1IIIb 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‐β1 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‐β1 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.