Platelet factor 4 (CXCL4) facilitates human macrophage infection with HIV-1 and potentiates virus replication

Abstract

Platelet factor 4 (CXCL4), a member of the CXC chemokine subfamily released in high amounts by activated platelets, has been identified as a monocyte survival factor that induces monocyte differentiation into macrophages. Although CXCL4 has been shown to have biological effects unique to chemokines, nothing is known about the role of CXCL4-derived human macrophages or CXCL4 in human immunodeficiency virus (HIV) disease. In this study, CXCL4-derived macrophages are compared with macrophage-colony stimulating factor (M-CSF)-derived macrophages for their ability to support HIV-1 replication. We show that CXCL4-derived macrophages can be infected with macrophage-tropic HIV-1 that uses either CC-chemokine receptor 5 (CCR5) or CXC-chemokine receptor 4 (CXCR4) as a co-receptor for viral entry. We also find that M-CSF and the chemokines, monocyte chemoattractant protein 1 (MCP-1; CCL2) and macrophage-inflammatory-protein-1-alpha (MIP-1alpha; CCL3) are produced upon R5- and X4-tropic HIV-1 replication in both M-CSF- and CXCL4-derived human macrophages. In addition, CXCL4 added to M-CSF-derived macrophages after virus adsorption and maintained throughout the infection enhances HIV-1 replication. We thus propose a novel role for CXCL4 in HIV disease.

Platelet activation suppresses HIV-1 infection of T cells

“…As a consequence, platelets might constantly release CXCL4, which would explain why viral load and platelet counts were found to be inversely correlated in infected humans [10] and why a direct correlation between CD62P levels and viral load was observed in a recent study [19]. However, it also needs to be noted that CXCL4 can increase HIV-1 replication in macrophages after successful viral entry into these cells [38], suggesting that CXCL4 might impact viral spread via more than one mechanism.…”

Alternative C-Terminal Helix Orientation Alters Chemokine Function

“…CXCL4 secreted from stimulated platelet exhibits a wide range of functions such regulation of hematopoiesis (19) and atherosclerosis (20 -22), antiangiogenesis (22)(23)(24)(25), chemotaxis (10,17), thrombocytopenia (26,27), anti-microbial activity (28,29), and inhibition of HIV-1 infection (30,31). G-protein-coupled receptors and cell surface glycosaminoglycans (GAGs) (14,32,33) are implicated in the aforementioned functions.…”

Serum amyloid A1 in combination with integrin αVβ3 increases glioblastoma cells mobility and progression

“…Serum biomarkers, S100A8, S100A9, and CXCL4, were identified from GBM patients' serum by using surface-enhanced laser desorption/ionization time-of-flight and liquid chromatography-MS/ MS technologies (Popescu et al, 2014). Their functions are correlated with acute inflammatory reactions to cancer cells (Basso et al, 2014;Gebhardt et al, 2006) and disease-related cystic fibrosis (van Bon et al, 2014;Schwartzkopff et al, 2009). We applied a similar proteomic methodology and found that the level of the SAA1 protein in the plasma of patients with GBM was higher than that in the plasma of healthy people; this was confirmed through protein blot analysis conducted on different cohorts.…”