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.

Infection of hematopoietic progenitor cells by HIV-1 subtype C, and its association with anemia in southern Africa

“…25,26,28 This disruption in the bone marrow microenvironment causes a loss of colony-forming cell growth, and disrupts proper hematopoietic lineage differentiation. 25,29,30 Work by multiple groups has shown that hematopoietic function can be at least partially restored with the use of highly active antiretroviral therapy (HAART). [31][32][33][34][35][36][37] The findings described here indicate that HIV-1C can infect HPC-CFUs and CD34 ϩ HPCs in vitro and in vivo, and that this infection is associated with higher anemia rates in infected patients.…”

Dengue 2 virus inhibitsin vitromegakaryocytic colony formation and induces apoptosis in thrombopoietin-inducible megakaryocytic differentiation from cord blood CD34+ cells

“…Importantly, the findings from the studies on the liquid cultures showed induction of apoptosis in the megakaryocytic progenitors exposed to dengue 2 virus and within a differentiation window of five days. Interestingly, induction of megakaryocyte apoptosis in vitro has been reported for other viruses like HIV-1 (Gibellini et al, 2007) and African swine fever virus (Gomez-Villamandos et al, 1998), where it has been proposed to be a major factor contributing towards thrombocytopenia associated with these infections. Further indepth studies are required to examine dengue virus-induced apoptosis of megakaryocytes based upon the present observations in order to elucidate its role as a factor affecting thrombopoiesis.…”

TGFβ-Mediated Downregulation of Thrombopoietin Is Associated With Platelet Decline in Asymptomatic SIV Infection

“…This is consistent with reports that TGFβ can directly arrest megakaryocyte maturation 13 and supports a dual role for TGFβ in platelet decline during asymptomatic infection, with TGFβ inhibiting megakaryocyte development and therefore decreasing platelet numbers both indirectly by decreasing the production of THPO and directly through TGFβ-mediated maturation arrest in megakaryocytes. Decreased megakaryocyte differentiation/maturation or defective platelet production secondary to direct lentiviral contact or infection may also contribute to decreased production 21,34 . Other mechanisms, such as platelet destruction secondary to platelet autoantibodies raised versus homologous lentiviral envelope proteins and sequestration of activated platelets in leukocyte-platelet aggregates, also have the potential to contribute to platelet decline 22,35,36 .…”

“…Similar elevations in plasma TGFβ level have been previously noted in HIV-infected patients compared with healthy controls, and associated with the progression of disease. 37 HIV-1 gp120 or Tat are sufficient to stimulate the production of TGFβ from hematopoietic stem cells or mammary epithelial cells in culture, respectively 21,38 . cART serves to suppress lentiviral replication and has been previously reported to decrease the level of TGFβ transcription in the lymph nodes of SIV-infected macaques 39 .…”

“…Though treatment with cART is generally sufficient to correct low platelet counts in HIV-infected individuals and is recommended as a first line of therapy 19 , the mechanism through which cART remedies low platelet count in the context of HIV infection has yet to be defined. Megakaryocytes can become infected with HIV 20 , but direct infection is not necessary to hinder platelet production; HIV-1 gp120 interactions with megakaryocyte CD4 inhibit megakaryocyte maturation and trigger megakaryocyte apoptosis 21 . cART furthermore serves to dampen the inflammatory response in HIV infection, which includes factors such as TGFβ and pf4 that downregulate THPO transcription, and, in the case of TGFβ, directly block megakaryocyte maturation 12,15,16 .…”